Children´s Interstitial Lung Disease, Diffuse Parenchymal Lung Disease, Interstitial Lung Disease
Conditions
Keywords
Childhood ILD, Fibrosing lung disease
Brief summary
This is an exploratory Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multinational study investigating the initiation or withdrawal of hydroxychloroquine in subjects with chILD.
Detailed description
This study is an explorative, prospective, randomized, double-blind, placebo controlled investigation of hydroxychloroquine (HCQ) in pediatric ILD. The treatments are organized in START and STOP blocks, which can be initiated in sequence, as needed by the subjects. Each patient can participate in each block only once. In the START block subjects are randomized to parallel-groups, then the placebo group is switched to active drug. In the STOP block, subjects on HCQ are randomized into parallel-groups treated with placebo or HCQ to investigate the withdrawal of HCQ for assessment of its efficacy.
Interventions
DRUGHydroxychloroquine sulfate
Apply drug to modify lysosomal pH
OTHERPlacebo
Apply Placebo not to modify lysosomal pH
Sponsors
Matthias Griese
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Placebo-bitter taste, same color and form capsule. Verum-same color, form capsule as placebo
Intervention model description
Goal of the study was to include all chILD patients who are planned to be, or are actively being, treated with HCQ. The character of this study is explorative. It was designed to closely accommodate the current clinical care situation.The study was an explorative, prospective, randomized, doubleblind, placebo-controlled investigation of HCQ in chILD and was one of the first investigator-initiated trials in this condition. The study contained two different study blocks, a START and a STOP block, which could be initiated in any sequence. Each patient can participate in each block only once. In the START block, subjects were randomized to parallel groups for 4 weeks treatment, then the placebo group switched to the active drug. In the STOP block, subjects taking HCQ were randomized into parallel groups (placebo or HCQ).
Eligibility
Sex/Gender
ALL
Age
3 Weeks to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Patients should be clinically stable during baseline (between Visit 1 and 2) for inclusion into the study 1. To determine this, attending physicians can use SpO2 in room air for patients on room air or on O2-supplement; the absolute difference on SpO2 is expected not to be ≥ 5% between Visit 1 and 2. For patients on respiratory support, the summary key parameters should not change ≥ 20% between Visit 1 and 2 and 2. No major changes in other medications between Visit 1 and 2 2. Mature newborn ≥ 37 weeks of gestation, age ≥ 3 wks and \<2y or Infants and children (≥2y and \< 18y) or Adults (≥18 and ≤30y) or Previously preterm (≤ 37 weeks of gestation) babies or children and adults of all ages if chILD genetically diagnosed (see inclusion criterion 3.) 3. Diagnosis of chronic (≥ 3 wks of duration) diffuse parenchymal lung disease (DPLD = chILD), defined in at least one of the following ways: 1. chILD genetically diagnosed surfactant dysfunction disorders including patients with mutations in SFTPC, SFTPB, ABCA3, TTF1 (Nkx2-1), further extremely rare entities with specific mutations, for example in TBX4, NPC2, NPC1, NPB, COPA, LRBA and other genes. In this case, also previously preterm (≤ 37 weeks of gestation) babies or children and adults of all ages can be included into the study. 2. chILD histologically diagnosed * Chronic pneumonitis of infancy (CPI) * Desquamative interstitial pneumonia (DIP) * Lipoid pneumonitis / Cholesterol pneumonia * Nonspecific interstitial pneumonia (NSIP) * PAP after the exclusion of mutations in GMCSF-Ra/b and GMCSF autoantibodies\* * Usual interstitial pneumonia (UIP) * Follicular bronchitis/bronchiolitis/Lymphocytic interstitial pneumonia (LIP) * Storage disease with primary pulmonary involvement (e.g. Niemann Pick) * Hermansky-Pudlak Syndrome * Idiopathic pulmonary haemorrhage (haemosiderosis)\* * Other histology diagnosing chILD, in particular combination of the above pattern, but not exclusively 4. Start block: no HCQ treatment in the last 12 weeks Stop block: stable HCQ treatment for at least the last 12 weeks 5. Ability of subject or/and legal representatives to understand character and individual consequences of clinical trial. 6. Signed and dated informed consent of the subject (if subject has the ability) and the representatives (of underaged children) must be available before start of any specific trial procedures. (\*may be diagnosed in the absence of a lung biopsy by characteristic lung lavage cytology (PAS stain, Fe stain), CT pattern or autoantibodies (gliadin, endomysium; cANCA) and clinical course.)
Exclusion criteria
Subjects presenting with any of the following criteria will not be included in the trial: * chILD primarily related to developmental disorders * chILD primarily related to growth abnormalities reflecting deficient alveolarisation * chILD related to chronic aspiration * chILD related to immunodeficiency * chILD related to abnormalities in lung vessel structure * chILD related to organ transplantation/organ rejection/GvHD * chILD related to recurrent infections * Acute severe infectious exacerbations * Known hypersensitivity to HCQ, or other ingredients of the tablets (lactose-monohydrate, povidone, maize starch, magnesium stearate, hypromellose, macrogol or titanium dioxide (E 171), silicon dioxide or mannitol), to sucrose-octaacetate or sodium saccharine. * Proven retinopathy or maculopathy * Glucose-6-phosphate-dehydrogenase deficiency resulting in favism or hemolytic anemia * Myasthenia gravis * Hematopoetic disorders * Pregnancy and lactation (Women with childbearing potential have to practice a medically accepted contraception during trial and till three months after the end of the treatment with HCQ, and a negative pregnancy test (serum or urine) should be existent on Visit 1, if girls of childbearing age and only if sexual relations are known or probable. It is at the discretion and responsibility of the attending physician to decide, whether a pregnancy test is necessary or not. Reliable contraception are systematic contraceptives (oral, implant, injection). Women that are sterile by surgery can participate in the trial. At the discretion of the investigator, sexual abstinence is also accepted as contraceptive method. Girls after menarche have to receive a counselling about birth control methods in presence of at least one parent, which has to be documented in the patient notes. * Participation in other clinical trials during the present clinical trial or not beyond the time of 4 half-lives of the medication used, at least one week. * Hereditary galactose intolerance, lactase deficiency or glucose-galactose- malabsorption * Renal insufficiency at screening, defined as glomerular filtration rate (GFR) * \< 40 mL/min/1.73 m2 in patients age 3 to 8 weeks * \< 60 mL/min/1.73 m2 in patients ≥ 8 weeks of age (KDIGO guideline 2012, K/DOQI guideline 2002) * Liver disease, gastrointestinal disorder, haematological disorder, epilepsy or other neurological disorder, psoriasis, porphyria at the discretion of the treating physician * Simultaneous prescription of other potentially nephrotoxic or hepatotoxic medication at the discretion of the treating physician
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks | O2 saturation measured after 5 min at rest and after withdrawal of oxygen if supplied. Change in Oxygenation (presence or absence of response to treatment) defined as change in O2 saturation \>=5%, or change in respiratory rate \>=20%, or change in respiratory support necessary |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of O2-sat in Room Air (%) | Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks | Oxygen saturation in room air at rest |
| Change of Respiratory Rate in Room Air (Breaths/Min) | Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks | Respiratory rate in room air at rest measured in breaths per minute |
| Change of Quality of Life (chILD Specific) | Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks | Quality of life (chILD specific) questionaire. A 5-point response scale was utilized (0 = never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; 4=almost always a problem). Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). Higher scores indicate better HrQoL. |
| Change of Quality of Life (Total Score) | Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks | Quality of life (total score) questionaire. A 5-point response scale was utilized (0 = never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; 4=almost always a problem). Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). Higher scores indicate better HrQoL. |
| Change of BMI Percentile | Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks | BMI percentile to adapt for age and sex related differences |
| Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks | O2 saturation measured after 5 min at rest and after withdrawal of oxygen if supplied. Change in Oxygenation (presence or absence of response to treatment) defined as change in O2 saturation \>=3%, or change in respiratory rate \>=20%, or change in respiratory support necessary |
| Absolute Change of Forced Vital Capacity (FVC) (% Predicted of the Reference Population) | Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks | FVC predicted expressed in % of the normal reference population (Quanjer PH, Brazzale DJ, Boros PW, et al. Implications of adopting the Global Lungs Initiative 2012 all-age reference equations for spirometry. Eur Respir J. 2013;42:1046-54.) The absolute change in FVC % predicited between two measurements is reported. |
| Absolute Change of Forced Expiratory Volume in One Second (FEV1) (% Predicted of the Reference Population) | Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks | FEV1 predicted expressed in % of the normal reference population (Quanjer PH, Brazzale DJ, Boros PW, et al. Implications of adopting the Global Lungs Initiative 2012 all-age reference equations for spirometry. Eur Respir J. 2013;42:1046-54.). The absolute change in FEV1 % predicited between two measurements is reported. |
| Absolute Change of Mean Expiratory Flow Between 25 and 75% of Vital Capacity (MEF25-75) (% Predicted of the Reference Population) | Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks | MEF25-75 predicted expressed in % of the normal reference population (Quanjer PH, Brazzale DJ, Boros PW, et al. Implications of adopting the Global Lungs Initiative 2012 all-age reference equations for spirometry. Eur Respir J. 2013;42:1046-54.). The absolute change in MEF25-75 % predicited between two measurements is reported. |
| Absolute Change of Six Minute Walking Test (6MWT) Distance (% Predicted of the Reference Population) | Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks | 6 Minute walking distance expressed as % of the predicted distance for age and sex. Ulrich et al, Reference values for the 6-minute walk test. BMC Pulm Med. 2013 Aug 5:13:49. doi: 10.1186/1471-2466-13-49. The absolute difference of two measuremnts between two time points is reported. |
| Change of LDH (U/ml) | Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks | Lactate dehydrogenase |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Start Placebo (Group A), Then Continue HCQ (Group C) Placebo for 4 weeks in a loading dose of 10 mg/kg bw/d, p.o., one daily dose in the evening for 7 days, then reduction to 6.5 mg/kg bw/d for 3 weeks; the maximum daily dose is 400 mg (Group A).
Followed by Hydroxychloroquine Sulfate (HCQ, Quensyl) in a loading dose of 10 mg/kg bw/d, p.o., one daily dose in the evening for 7 days, then reduction to 6.5 mg/kg bw/d for 3 weeks; the maximum daily dose is 400 mg. (Group C). | 17 |
| Start HCQ (Group B), Then Continue HCQ (Group D) Hydroxychloroquine Sulfate (HCQ, Quensyl) in a loading dose of 10 mg/kg bw/d, p.o., one daily dose in the evening for 7 days, then reduction to 6.5 mg/kg bw/d for 3 weeks; the maximum daily dose is 400 mg (Group B).
Followed by HCQ for 4 weeks (Group D) | 9 |
| Stop HCQ (Group E), Then Continued no Medication (Group G) Individual dose, usually Hydroxychloroquine Sulfate (HCQ, Quensyl) 6-10 mg/kg bw/d, p.o., one daily dose in the evening; the maximum daily dose is 400 mg. The dose, on which the patient is included into the trial, was continued for 3 months. After therapy of 3 months the medication will be stopped. (Group E) The patient will be followed up for additional 3 months on no medication. (Group G) | 4 |
| Stop Placebo (Group F), Then Continued no Medication (Group H) PLACEBO (given according to the individual dose the patient used to take as usually Hydroxychloroquine Sulfate (HCQ, Quensyl) before 6-10 mg/kg bw/d, p.o., one daily dose in the evening; the maximum daily dose is 400 mg. The dose, on which the patient is included into the trial, was continued for 3 months. After therapy of 3 months the PLACEBO will be stopped. (Group F) The patient will be followed up for additional 3 months on no medication. (Group H) | 5 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| First 4 Wks Start, First 3 Mon Stop | Physician Decision | 3 | 2 | 0 | 0 |
| First 4 Wks Start, First 3 Mon Stop | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Start Placebo (Group A), Then Continue HCQ (Group C) | Start HCQ (Group B), Then Continue HCQ (Group D) | Stop HCQ (Group E), Then Continued no Medication (Group G) | Stop Placebo (Group F), Then Continued no Medication (Group H) |
|---|---|---|---|---|---|
| Age, Customized | 0 n amount of patients | 9 n amount of patients | 7.8 n amount of patients | 8.2 n amount of patients | 9.2 n amount of patients |
| O2 sat [%] | 0 % 02 saturation | 92.6 % 02 saturation | 93.9 % 02 saturation | 93.7 % 02 saturation | 94.8 % 02 saturation |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 16 Participants | 9 Participants | 4 Participants | 5 Participants |
| Region of Enrollment Germany | 35 participants | 17 participants | 9 participants | 4 participants | 5 participants |
| Sex: Female, Male Female | 22 Participants | 10 Participants | 7 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 13 Participants | 7 Participants | 2 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 7 | 0 / 4 | 0 / 5 |
| other Total, other adverse events | 12 / 13 | 7 / 7 | 4 / 4 | 5 / 5 |
| serious Total, serious adverse events | 1 / 13 | 0 / 7 | 0 / 4 | 0 / 5 |
Outcome results
Primary
Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary
O2 saturation measured after 5 min at rest and after withdrawal of oxygen if supplied. Change in Oxygenation (presence or absence of response to treatment) defined as change in O2 saturation \>=5%, or change in respiratory rate \>=20%, or change in respiratory support necessary
Time frame: Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Population: Group D received HCQ for 4 weeks. These patients had also previously as group B 4 weeks of HCQ, thus an exposure of 8 weeks. This was not deemed comparable to 4 weeks of placebo. Group H received no medication for 3 months. These patients had already withdrawal of HCQ for 3 months as group F, thus no HCQ exposure for 6 months. This was not deemed comparable to 3 months on HCQ. The data of groups D and H were thus not used for the indicated statistical comparisons.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Start Placebo, Then HCQ (Group A) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 0 Participants |
| Start Placebo, Then HCQ (Group A) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 13 Participants |
| Start HCQ, Then HCQ (Group B) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 0 Participants |
| Start HCQ, Then HCQ (Group B) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 7 Participants |
| Start Placebo, Then HCQ (Group C) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 3 Participants |
| Start Placebo, Then HCQ (Group C) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 9 Participants |
| Start HCQ, Then HCQ (Group D) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 0 Participants |
| Start HCQ, Then HCQ (Group D) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 7 Participants |
| Stop HCQ, Then no Medication (Group E) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 0 Participants |
| Stop HCQ, Then no Medication (Group E) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 3 Participants |
| Stop Placebo, Then no Medication (Group F) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 0 Participants |
| Stop Placebo, Then no Medication (Group F) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 5 Participants |
| Stop HCQ, Then no Medication (Group G) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 2 Participants |
| Stop HCQ, Then no Medication (Group G) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 1 Participants |
| Stop Placebo, Then no Medication (Group H) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 1 Participants |
| Stop Placebo, Then no Medication (Group H) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=5%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 4 Participants |
p-value: 1Fisher Exact
p-value: 1Fisher Exact
Secondary
Absolute Change of Forced Expiratory Volume in One Second (FEV1) (% Predicted of the Reference Population)
FEV1 predicted expressed in % of the normal reference population (Quanjer PH, Brazzale DJ, Boros PW, et al. Implications of adopting the Global Lungs Initiative 2012 all-age reference equations for spirometry. Eur Respir J. 2013;42:1046-54.). The absolute change in FEV1 % predicited between two measurements is reported.
Time frame: Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Population: Group D received HCQ for 4 weeks. These patients had also previously as group B 4 weeks of HCQ, thus an exposure of 8 weeks. This was not deemed comparable to 4 weeks of placebo. Group H received no medication for 3 months. These patients had already withdrawal of HCQ for 3 months as group F, thus no HCQ exposure for 6 months. This was not deemed comparable to 3 months on HCQ. The data of groups D and H were thus not used for the indicated statistical comparisons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Start Placebo, Then HCQ (Group A) | Absolute Change of Forced Expiratory Volume in One Second (FEV1) (% Predicted of the Reference Population) | 0.6 percentage of reference population | Standard Deviation 4.1 |
| Start HCQ, Then HCQ (Group B) | Absolute Change of Forced Expiratory Volume in One Second (FEV1) (% Predicted of the Reference Population) | 2.0 percentage of reference population | Standard Deviation 13.1 |
| Start Placebo, Then HCQ (Group C) | Absolute Change of Forced Expiratory Volume in One Second (FEV1) (% Predicted of the Reference Population) | 9.0 percentage of reference population | Standard Deviation 18.6 |
| Start HCQ, Then HCQ (Group D) | Absolute Change of Forced Expiratory Volume in One Second (FEV1) (% Predicted of the Reference Population) | 0.5 percentage of reference population | Standard Deviation 5.1 |
| Stop HCQ, Then no Medication (Group E) | Absolute Change of Forced Expiratory Volume in One Second (FEV1) (% Predicted of the Reference Population) | 0.0 percentage of reference population | Standard Deviation 4.4 |
| Stop Placebo, Then no Medication (Group F) | Absolute Change of Forced Expiratory Volume in One Second (FEV1) (% Predicted of the Reference Population) | -0.5 percentage of reference population | Standard Deviation 0.7 |
| Stop HCQ, Then no Medication (Group G) | Absolute Change of Forced Expiratory Volume in One Second (FEV1) (% Predicted of the Reference Population) | -1.0 percentage of reference population | Standard Deviation 4.4 |
| Stop Placebo, Then no Medication (Group H) | Absolute Change of Forced Expiratory Volume in One Second (FEV1) (% Predicted of the Reference Population) | 5.5 percentage of reference population | Standard Deviation 4.9 |
p-value: 0.8595% CI: [-1, 1.4]t-test, 2 sided
p-value: 0.25895% CI: [-0.4, 1.6]t-test, 2 sided
p-value: 0.86295% CI: [-1.9, 1.7]t-test, 2 sided
p-value: 0.8495% CI: [-1.8, 1.4]t-test, 2 sided
Secondary
Absolute Change of Forced Vital Capacity (FVC) (% Predicted of the Reference Population)
FVC predicted expressed in % of the normal reference population (Quanjer PH, Brazzale DJ, Boros PW, et al. Implications of adopting the Global Lungs Initiative 2012 all-age reference equations for spirometry. Eur Respir J. 2013;42:1046-54.) The absolute change in FVC % predicited between two measurements is reported.
Time frame: Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Population: Group D received HCQ for 4 weeks. These patients had also previously as group B 4 weeks of HCQ, thus an exposure of 8 weeks. This was not deemed comparable to 4 weeks of placebo. Group H received no medication for 3 months. These patients had already withdrawal of HCQ for 3 months as group F, thus no HCQ exposure for 6 months. This was not deemed comparable to 3 months on HCQ. The data of groups D and H were thus not used for the indicated statistical comparisons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Start Placebo, Then HCQ (Group A) | Absolute Change of Forced Vital Capacity (FVC) (% Predicted of the Reference Population) | 0.0 percentage of reference population | Standard Deviation 3.7 |
| Start HCQ, Then HCQ (Group B) | Absolute Change of Forced Vital Capacity (FVC) (% Predicted of the Reference Population) | 2.5 percentage of reference population | Standard Deviation 13 |
| Start Placebo, Then HCQ (Group C) | Absolute Change of Forced Vital Capacity (FVC) (% Predicted of the Reference Population) | 10.6 percentage of reference population | Standard Deviation 19.7 |
| Start HCQ, Then HCQ (Group D) | Absolute Change of Forced Vital Capacity (FVC) (% Predicted of the Reference Population) | -1.0 percentage of reference population | Standard Deviation 4.2 |
| Stop HCQ, Then no Medication (Group E) | Absolute Change of Forced Vital Capacity (FVC) (% Predicted of the Reference Population) | 2.3 percentage of reference population | Standard Deviation 7.6 |
| Stop Placebo, Then no Medication (Group F) | Absolute Change of Forced Vital Capacity (FVC) (% Predicted of the Reference Population) | 0.5 percentage of reference population | Standard Deviation 2.1 |
| Stop HCQ, Then no Medication (Group G) | Absolute Change of Forced Vital Capacity (FVC) (% Predicted of the Reference Population) | -1.3 percentage of reference population | Standard Deviation 5.1 |
| Stop Placebo, Then no Medication (Group H) | Absolute Change of Forced Vital Capacity (FVC) (% Predicted of the Reference Population) | 4.5 percentage of reference population | Standard Deviation 4.9 |
p-value: 0.7395% CI: [-0.9, 1.5]t-test, 2 sided
p-value: 0.1795% CI: [-0.3, 1.8]t-test, 2 sided
p-value: 0.72495% CI: [-2.1, 1.5]t-test, 2 sided
p-value: 0.48795% CI: [-2.2, 1.1]t-test, 2 sided
Secondary
Absolute Change of Mean Expiratory Flow Between 25 and 75% of Vital Capacity (MEF25-75) (% Predicted of the Reference Population)
MEF25-75 predicted expressed in % of the normal reference population (Quanjer PH, Brazzale DJ, Boros PW, et al. Implications of adopting the Global Lungs Initiative 2012 all-age reference equations for spirometry. Eur Respir J. 2013;42:1046-54.). The absolute change in MEF25-75 % predicited between two measurements is reported.
Time frame: Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Population: Group D received HCQ for 4 weeks. These patients had also previously as group B 4 weeks of HCQ, thus an exposure of 8 weeks. This was not deemed comparable to 4 weeks of placebo. Group H received no medication for 3 months. These patients had already withdrawal of HCQ for 3 months as group F, thus no HCQ exposure for 6 months. This was not deemed comparable to 3 months on HCQ. The data of groups D and H were thus not used for the indicated statistical comparisons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Start Placebo, Then HCQ (Group A) | Absolute Change of Mean Expiratory Flow Between 25 and 75% of Vital Capacity (MEF25-75) (% Predicted of the Reference Population) | 3.0 percentage of reference population | Standard Deviation 13.1 |
| Start HCQ, Then HCQ (Group B) | Absolute Change of Mean Expiratory Flow Between 25 and 75% of Vital Capacity (MEF25-75) (% Predicted of the Reference Population) | -14.8 percentage of reference population | Standard Deviation 15.2 |
| Start Placebo, Then HCQ (Group C) | Absolute Change of Mean Expiratory Flow Between 25 and 75% of Vital Capacity (MEF25-75) (% Predicted of the Reference Population) | -2.6 percentage of reference population | Standard Deviation 8.6 |
| Start HCQ, Then HCQ (Group D) | Absolute Change of Mean Expiratory Flow Between 25 and 75% of Vital Capacity (MEF25-75) (% Predicted of the Reference Population) | 18.5 percentage of reference population | Standard Deviation 17.4 |
| Stop HCQ, Then no Medication (Group E) | Absolute Change of Mean Expiratory Flow Between 25 and 75% of Vital Capacity (MEF25-75) (% Predicted of the Reference Population) | -8.7 percentage of reference population | Standard Deviation 14.2 |
| Stop Placebo, Then no Medication (Group F) | Absolute Change of Mean Expiratory Flow Between 25 and 75% of Vital Capacity (MEF25-75) (% Predicted of the Reference Population) | -7.0 percentage of reference population | Standard Deviation 1.4 |
| Stop HCQ, Then no Medication (Group G) | Absolute Change of Mean Expiratory Flow Between 25 and 75% of Vital Capacity (MEF25-75) (% Predicted of the Reference Population) | -11.3 percentage of reference population | Standard Deviation 7.8 |
| Stop Placebo, Then no Medication (Group H) | Absolute Change of Mean Expiratory Flow Between 25 and 75% of Vital Capacity (MEF25-75) (% Predicted of the Reference Population) | 15.5 percentage of reference population | Standard Deviation 6.4 |
p-value: 0.0195% CI: [-2.6, 0]t-test, 2 sided
p-value: 0.53395% CI: [-1.5, 0.5]t-test, 2 sided
p-value: 0.85895% CI: [-1.6, 1.9]t-test, 2 sided
p-value: 0.66195% CI: [-1.4, 1.8]t-test, 2 sided
Secondary
Absolute Change of Six Minute Walking Test (6MWT) Distance (% Predicted of the Reference Population)
6 Minute walking distance expressed as % of the predicted distance for age and sex. Ulrich et al, Reference values for the 6-minute walk test. BMC Pulm Med. 2013 Aug 5:13:49. doi: 10.1186/1471-2466-13-49. The absolute difference of two measuremnts between two time points is reported.
Time frame: Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Population: Group D received HCQ for 4 weeks. These patients had also previously as group B 4 weeks of HCQ, thus an exposure of 8 weeks. This was not deemed comparable to 4 weeks of placebo. Group H received no medication for 3 months. These patients had already withdrawal of HCQ for 3 months as group F, thus no HCQ exposure for 6 months. This was not deemed comparable to 3 months on HCQ. The data of groups D and H were thus not used for the indicated statistical comparisons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Start Placebo, Then HCQ (Group A) | Absolute Change of Six Minute Walking Test (6MWT) Distance (% Predicted of the Reference Population) | -0.8 percentage of reference population | Standard Deviation 3.6 |
| Start HCQ, Then HCQ (Group B) | Absolute Change of Six Minute Walking Test (6MWT) Distance (% Predicted of the Reference Population) | -31.0 percentage of reference population | — |
| Start Placebo, Then HCQ (Group C) | Absolute Change of Six Minute Walking Test (6MWT) Distance (% Predicted of the Reference Population) | 0.8 percentage of reference population | Standard Deviation 2.1 |
| Start HCQ, Then HCQ (Group D) | Absolute Change of Six Minute Walking Test (6MWT) Distance (% Predicted of the Reference Population) | 44 percentage of reference population | — |
| Stop HCQ, Then no Medication (Group E) | Absolute Change of Six Minute Walking Test (6MWT) Distance (% Predicted of the Reference Population) | 0.3 percentage of reference population | Standard Deviation 8.5 |
| Stop Placebo, Then no Medication (Group F) | Absolute Change of Six Minute Walking Test (6MWT) Distance (% Predicted of the Reference Population) | -0.5 percentage of reference population | Standard Deviation 2.1 |
| Stop HCQ, Then no Medication (Group G) | Absolute Change of Six Minute Walking Test (6MWT) Distance (% Predicted of the Reference Population) | 8.7 percentage of reference population | Standard Deviation 12.6 |
| Stop Placebo, Then no Medication (Group H) | Absolute Change of Six Minute Walking Test (6MWT) Distance (% Predicted of the Reference Population) | -3.0 percentage of reference population | Standard Deviation 2.8 |
95% CI: [-14, -2.7]
p-value: 0.57695% CI: [-0.9, 2]t-test, 2 sided
p-value: 0.88495% CI: [-1.9, 1.7]t-test, 2 sided
p-value: 0.56395% CI: [-2.4, 0.9]t-test, 2 sided
Secondary
Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary
O2 saturation measured after 5 min at rest and after withdrawal of oxygen if supplied. Change in Oxygenation (presence or absence of response to treatment) defined as change in O2 saturation \>=3%, or change in respiratory rate \>=20%, or change in respiratory support necessary
Time frame: Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Population: Group D received HCQ for 4 weeks. These patients had also previously as group B 4 weeks of HCQ, thus an exposure of 8 weeks. This was not deemed comparable to 4 weeks of placebo. Group H received no medication for 3 months. These patients had already withdrawal of HCQ for 3 months as group F, thus no HCQ exposure for 6 months. This was not deemed comparable to 3 months on HCQ. The data of groups D and H were thus not used for the indicated statistical comparisons.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Start Placebo, Then HCQ (Group A) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 2 Participants |
| Start Placebo, Then HCQ (Group A) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 11 Participants |
| Start HCQ, Then HCQ (Group B) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 1 Participants |
| Start HCQ, Then HCQ (Group B) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 5 Participants |
| Start Placebo, Then HCQ (Group C) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 2 Participants |
| Start Placebo, Then HCQ (Group C) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 10 Participants |
| Start HCQ, Then HCQ (Group D) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 0 Participants |
| Start HCQ, Then HCQ (Group D) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 6 Participants |
| Stop HCQ, Then no Medication (Group E) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 0 Participants |
| Stop HCQ, Then no Medication (Group E) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 3 Participants |
| Stop Placebo, Then no Medication (Group F) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 3 Participants |
| Stop Placebo, Then no Medication (Group F) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 2 Participants |
| Stop HCQ, Then no Medication (Group G) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 2 Participants |
| Stop HCQ, Then no Medication (Group G) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 1 Participants |
| Stop Placebo, Then no Medication (Group H) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Responder | 1 Participants |
| Stop Placebo, Then no Medication (Group H) | Change in Oxygenation (Presence or Absence of Response to Treatment) Defined as Change in O2 Saturation >=3%, or Change in Respiratory Rate >=20%, or Change in Respiratory Support Necessary | Non-responder | 4 Participants |
p-value: 11.1% CI: [0.079, 15.16]Fisher Exact
p-value: 195% CI: [-0.34, 0.008]McNemar
p-value: 0.196Fisher Exact
Secondary
Change of BMI Percentile
BMI percentile to adapt for age and sex related differences
Time frame: Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Population: Group D received HCQ for 4 weeks. These patients had also previously as group B 4 weeks of HCQ, thus an exposure of 8 weeks. This was not deemed comparable to 4 weeks of placebo. Group H received no medication for 3 months. These patients had already withdrawal of HCQ for 3 months as group F, thus no HCQ exposure for 6 months. This was not deemed comparable to 3 months on HCQ. The data of groups D and H were thus not used for the indicated statistical comparisons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Start Placebo, Then HCQ (Group A) | Change of BMI Percentile | 7.5 percentile | Standard Deviation 11.7 |
| Start HCQ, Then HCQ (Group B) | Change of BMI Percentile | -1.8 percentile | Standard Deviation 5.1 |
| Start Placebo, Then HCQ (Group C) | Change of BMI Percentile | -1.6 percentile | Standard Deviation 8.1 |
| Start HCQ, Then HCQ (Group D) | Change of BMI Percentile | 22.6 percentile | Standard Deviation 43.7 |
| Stop HCQ, Then no Medication (Group E) | Change of BMI Percentile | -3.3 percentile | Standard Deviation 7.9 |
| Stop Placebo, Then no Medication (Group F) | Change of BMI Percentile | 2.2 percentile | Standard Deviation 11.4 |
| Stop HCQ, Then no Medication (Group G) | Change of BMI Percentile | 13.3 percentile | Standard Deviation 20.9 |
| Stop Placebo, Then no Medication (Group H) | Change of BMI Percentile | 3.9 percentile | Standard Deviation 9.2 |
p-value: 0.02495% CI: [-1.9, 0]t-test, 2 sided
p-value: 0.04595% CI: [-1.7, -0.1]t-test, 2 sided
p-value: 0.45895% CI: [-0.9, 2]t-test, 2 sided
p-value: 0.421695% CI: [-2.8, 0.7]t-test, 2 sided
Secondary
Change of LDH (U/ml)
Lactate dehydrogenase
Time frame: Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Population: There was no blood sampled at the visit at the end of group G and H, thus no values available. Group D received HCQ for 4 weeks. These patients had also previously as group B 4 weeks of HCQ, thus an exposure of 8 weeks. This was not deemed comparable to 4 weeks of placebo. This was not deemed comparable to 3 months on HCQ. The data of groups D and H were thus not used for the indicated statistical comparisons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Start Placebo, Then HCQ (Group A) | Change of LDH (U/ml) | -28.2 Enzyme activity units per ml | Standard Deviation 53.7 |
| Start HCQ, Then HCQ (Group B) | Change of LDH (U/ml) | 43.0 Enzyme activity units per ml | Standard Deviation 61 |
| Start Placebo, Then HCQ (Group C) | Change of LDH (U/ml) | 11.3 Enzyme activity units per ml | Standard Deviation 67 |
| Start HCQ, Then HCQ (Group D) | Change of LDH (U/ml) | -32.2 Enzyme activity units per ml | Standard Deviation 55.3 |
| Stop HCQ, Then no Medication (Group E) | Change of LDH (U/ml) | 34.5 Enzyme activity units per ml | Standard Deviation 0.7 |
| Stop Placebo, Then no Medication (Group F) | Change of LDH (U/ml) | 9.3 Enzyme activity units per ml | Standard Deviation 65.5 |
p-value: 0.06395% CI: [0.1, 2.5]t-test, 2 sided
p-value: 0.4195% CI: [-0.3, 1.6]t-test, 2 sided
p-value: 0.57495% CI: [-2.3, 1.3]t-test, 2 sided
Secondary
Change of O2-sat in Room Air (%)
Oxygen saturation in room air at rest
Time frame: Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Population: Group D received HCQ for 4 weeks. These patients had also previously as group B 4 weeks of HCQ, thus an exposure of 8 weeks. This was not deemed comparable to 4 weeks of placebo. Group H received no medication for 3 months. These patients had already withdrawal of HCQ for 3 months as group F, thus no HCQ exposure for 6 months. This was not deemed comparable to 3 months on HCQ. The data of groups D and H were thus not used for the indicated statistical comparisons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Start Placebo, Then HCQ (Group A) | Change of O2-sat in Room Air (%) | -0.1 percentage of O2 Sat | Standard Deviation 2.4 |
| Start HCQ, Then HCQ (Group B) | Change of O2-sat in Room Air (%) | -0.6 percentage of O2 Sat | Standard Deviation 3.3 |
| Start Placebo, Then HCQ (Group C) | Change of O2-sat in Room Air (%) | 1.8 percentage of O2 Sat | Standard Deviation 3.5 |
| Start HCQ, Then HCQ (Group D) | Change of O2-sat in Room Air (%) | -1.7 percentage of O2 Sat | Standard Deviation 2.6 |
| Stop HCQ, Then no Medication (Group E) | Change of O2-sat in Room Air (%) | 0.3 percentage of O2 Sat | Standard Deviation 1.2 |
| Stop Placebo, Then no Medication (Group F) | Change of O2-sat in Room Air (%) | -2.4 percentage of O2 Sat | Standard Deviation 2.7 |
| Stop HCQ, Then no Medication (Group G) | Change of O2-sat in Room Air (%) | -3.7 percentage of O2 Sat | Standard Deviation 6.4 |
| Stop Placebo, Then no Medication (Group H) | Change of O2-sat in Room Air (%) | 0.2 percentage of O2 Sat | Standard Deviation 4.8 |
p-value: 0.75795% CI: [-1.2, 0.8]t-test, 2 sided
p-value: 0.22995% CI: [-0.2, 1.1]t-test, 2 sided
p-value: 0.09795% CI: [-2.7, 0.4]t-test, 2 sided
p-value: 0.42795% CI: [-2.5, 0.8]t-test, 2 sided
Secondary
Change of Quality of Life (chILD Specific)
Quality of life (chILD specific) questionaire. A 5-point response scale was utilized (0 = never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; 4=almost always a problem). Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). Higher scores indicate better HrQoL.
Time frame: Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Population: Group D received HCQ for 4 weeks. These patients had also previously as group B 4 weeks of HCQ, thus an exposure of 8 weeks. This was not deemed comparable to 4 weeks of placebo. Group H received no medication for 3 months. These patients had already withdrawal of HCQ for 3 months as group F, thus no HCQ exposure for 6 months. This was not deemed comparable to 3 months on HCQ. The data of groups D and H were thus not used for the indicated statistical comparisons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Start Placebo, Then HCQ (Group A) | Change of Quality of Life (chILD Specific) | 6.9 score on a scale | Standard Deviation 9.6 |
| Start HCQ, Then HCQ (Group B) | Change of Quality of Life (chILD Specific) | 0.1 score on a scale | Standard Deviation 3.18 |
| Start Placebo, Then HCQ (Group C) | Change of Quality of Life (chILD Specific) | -3.2 score on a scale | Standard Deviation 4.8 |
| Start HCQ, Then HCQ (Group D) | Change of Quality of Life (chILD Specific) | -9.1 score on a scale | Standard Deviation 3.25 |
| Stop HCQ, Then no Medication (Group E) | Change of Quality of Life (chILD Specific) | -5.7 score on a scale | Standard Deviation 11.2 |
| Stop Placebo, Then no Medication (Group F) | Change of Quality of Life (chILD Specific) | 7.5 score on a scale | Standard Deviation 2.3 |
| Stop HCQ, Then no Medication (Group G) | Change of Quality of Life (chILD Specific) | 2.3 score on a scale | Standard Deviation 3.2 |
| Stop Placebo, Then no Medication (Group H) | Change of Quality of Life (chILD Specific) | -2.0 score on a scale | Standard Deviation 12.3 |
p-value: 0.17895% CI: [-2.4, 0.9]t-test, 2 sided
p-value: 0.1195% CI: [-2.6, -0.1]t-test, 2 sided
p-value: 0.33895% CI: [-0.6, 3.9]t-test, 2 sided
p-value: 0.397995% CI: [-3, 1.1]t-test, 2 sided
Secondary
Change of Quality of Life (Total Score)
Quality of life (total score) questionaire. A 5-point response scale was utilized (0 = never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; 4=almost always a problem). Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). Higher scores indicate better HrQoL.
Time frame: Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Population: Group D received HCQ for 4 weeks. These patients had also previously as group B 4 weeks of HCQ, thus an exposure of 8 weeks. This was not deemed comparable to 4 weeks of placebo. Group H received no medication for 3 months. These patients had already withdrawal of HCQ for 3 months as group F, thus no HCQ exposure for 6 months. This was not deemed comparable to 3 months on HCQ. The data of groups D and H were thus not used for the indicated statistical comparisons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Start Placebo, Then HCQ (Group A) | Change of Quality of Life (Total Score) | 0.4 score on a scale | Standard Deviation 6.9 |
| Start HCQ, Then HCQ (Group B) | Change of Quality of Life (Total Score) | 0.3 score on a scale | Standard Deviation 1.2 |
| Start Placebo, Then HCQ (Group C) | Change of Quality of Life (Total Score) | 4.8 score on a scale | Standard Deviation 4.3 |
| Start HCQ, Then HCQ (Group D) | Change of Quality of Life (Total Score) | 0.4 score on a scale | Standard Deviation 7 |
| Stop HCQ, Then no Medication (Group E) | Change of Quality of Life (Total Score) | 9.2 score on a scale | Standard Deviation 5.4 |
| Stop Placebo, Then no Medication (Group F) | Change of Quality of Life (Total Score) | -9.5 score on a scale | Standard Deviation 8.8 |
| Stop HCQ, Then no Medication (Group G) | Change of Quality of Life (Total Score) | -1.7 score on a scale | Standard Deviation 2.3 |
| Stop Placebo, Then no Medication (Group H) | Change of Quality of Life (Total Score) | -5.5 score on a scale | Standard Deviation 4.3 |
p-value: 0.96595% CI: [-1.6, 1.6]t-test, 2 sided
p-value: 0.37495% CI: [-0.4, 1.9]t-test, 2 sided
p-value: 0.14995% CI: [-5.2, 0.1]t-test, 2 sided
p-value: 0.296395% CI: [0, 5.3]t-test, 2 sided
Secondary
Change of Respiratory Rate in Room Air (Breaths/Min)
Respiratory rate in room air at rest measured in breaths per minute
Time frame: Start block: A,B after 4 and C,D after 8 weeks; Stop block: E,F after 12 and G,H after 24 weeks
Population: Group D received HCQ for 4 weeks. These patients had also previously as group B 4 weeks of HCQ, thus an exposure of 8 weeks. This was not deemed comparable to 4 weeks of placebo. Group H received no medication for 3 months. These patients had already withdrawal of HCQ for 3 months as group F, thus no HCQ exposure for 6 months. This was not deemed comparable to 3 months on HCQ. The data of groups D and H were thus not used for the indicated statistical comparisons.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Start Placebo, Then HCQ (Group A) | Change of Respiratory Rate in Room Air (Breaths/Min) | 1.2 breaths/min | Standard Deviation 5.4 |
| Start HCQ, Then HCQ (Group B) | Change of Respiratory Rate in Room Air (Breaths/Min) | 0.2 breaths/min | Standard Deviation 0.4 |
| Start Placebo, Then HCQ (Group C) | Change of Respiratory Rate in Room Air (Breaths/Min) | -1.3 breaths/min | Standard Deviation 5.6 |
| Start HCQ, Then HCQ (Group D) | Change of Respiratory Rate in Room Air (Breaths/Min) | 13.8 breaths/min | Standard Deviation 33.1 |
| Stop HCQ, Then no Medication (Group E) | Change of Respiratory Rate in Room Air (Breaths/Min) | -2.7 breaths/min | Standard Deviation 1.2 |
| Stop Placebo, Then no Medication (Group F) | Change of Respiratory Rate in Room Air (Breaths/Min) | -5.4 breaths/min | Standard Deviation 9.4 |
| Stop HCQ, Then no Medication (Group G) | Change of Respiratory Rate in Room Air (Breaths/Min) | 7.3 breaths/min | Standard Deviation 5 |
| Stop Placebo, Then no Medication (Group H) | Change of Respiratory Rate in Room Air (Breaths/Min) | 2.5 breaths/min | Standard Deviation 7.9 |
p-value: 0.54395% CI: [-1.2, 0.8]t-test, 2 sided
p-value: 0.42195% CI: [-1.2, 0.3]t-test, 2 sided
p-value: 0.55395% CI: [-1.8, 1.1]t-test, 2 sided
p-value: 0.10295% CI: [-5, -0.5]t-test, 2 sided