Scleroderma, Diffuse, Scleroderma, Systemic, Sclerosis, Systemic
Conditions
Brief summary
FT011 is an anti-fibrotic drug that is being tested as a treatment for scleroderma. This study is being conducted to see what the body does to the drug (pharmacokinetics), and what the drug does to the body (pharmacodynamics).
Interventions
DRUGFT011
Two x 100mg capsules once daily for 12 weeks
DRUGPlacebo
Two placebo capsules once daily for 12 weeks
Sponsors
Certa Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Provide written informed consent prior to any study procedures and who agree to adhere to all protocol requirements. 2. Aged 18 to 75 years inclusive at the time of consent. 3. Have a classification of systemic sclerosis, as defined by American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria with disease duration ≤10 years from first non-Raynaud phenomenon manifestation. 4. Have a diagnosis of diffuse cutaneous SSc defined as systemic sclerosis with skin thickening on the upper arms proximal to the elbows, on the upper legs proximal to the knees, or on the trunk. 5. Have skin thickening in a body area suitable for repeat biopsy. 6. Have a mRSS at Screening of ≥15 to ≤40. 7. FVC ≥50% of predicted at Screening. 8. If on azathioprine, mycophenolate mofetil, or hydroxychloroquine, have been on a stable dose for at least 2 months prior to baseline. 9. Women of childbearing potential (WOCPB) and males with partners of child-bearing potential must agree to use highly effective contraception (a failure rate of \<1%), for the duration of the study and until three months after their last dose of IMP.
Exclusion criteria
1. Pregnant or breast-feeding, or plan to become pregnant during the study. 2. Have received any IMP within 30 days or 5 half-lives prior to randomisation (4 months if the previous drug was a new chemical entity), whichever is longer. 3. Have known or suspected contraindications to the IMP. 4. Have severe or unstable SSc or end-stage organ involvement as evidenced by: 1. On an organ transplantation list or has received an organ transplant including autologous stem cell transplant. 2. Renal crisis within 1 year prior to Baseline. 5. Interstitial lung disease or pulmonary hypertension requiring constant oxygen therapy. This excludes oxygen used to aid sleep or exercise. 6. Gastrointestinal dysmotility requiring total parenteral nutrition or requiring hospitalisation within the 6 months prior to Baseline. 7. Concomitant inflammatory myositis, rheumatoid arthritis, or systemic lupus erythematosus when definite classification criteria for those diseases are met (Bohan and Peter criteria for polymyositis and dermatomyositis) 8. SSc-like illnesses related to exposures or ingestions 9. The use of the following drugs within the specified periods: 1. Methotrexate in the 2 weeks prior to Day 1 2. Other anti-fibrotic agents including D-penicillamine or tyrosine kinase inhibitors (nilotinib, imatinib, dasatinib) in the month prior to Screening. 3. Biologic drugs such as tumour necrosing factor (TNF) inhibitors, tocilizumab, or Janus kinase (JAK) inhibitors, in the 3 months prior to Screening. 4. Rituximab in the 6 months prior to Screening. 5. Cyclophosphamide oral or IV in the 3 months prior to Screening. 6. Oral prednisolone \>10 mg per day or IV steroids in the month prior to Screening. 10. Have any malignancy not considered cured (except basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix); a subject is considered cured if there has been no evidence of cancer recurrence for the 6 years prior to randomisation. 11. Have aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), or bilirubin values above the upper limit of normal (ULN) at Screening or Baseline, or evidence of hepatic disease as determined by any one of the following: history of hepatic encephalopathy, history of oesophageal varices, or history of portacaval shunt. 12. Estimated glomerular filtration rate (eGFR) \<60mL/min, urinary albumin/creatinine ratio \>30mg/g. 13. Haemoglobin \< 80 g/L, platelets \< 90 x 109/L, or neutrophil count \< 1.4 x 109/L 14. Other than SSc, have any other medical condition or significant co-morbidities, clinically relevant social or psychiatric conditions, or any finding during Screening, which in the investigator's opinion may put the subject at risk or interfere with the study objectives.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FT011 Levels in Plasma | Mean of cmax post first dose and cmax post last dose | Measurement of maximum concentration (cmax) of FT011. First dose Cmax and last dose Cmax for each participant were averaged together to calculate a single mean Cmax for each treatment arm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) From Baseline to End of Study | Baseline to Week 16 | TEAEs per arm during study treatment and follow up periods |
| mRSS Change From Baseline | End of treatment (week 12) | The mRSS is a validated physical evaluation of patient's skin thickness rated by clinical palpation using a 0-3 scale (0 = normal skin; 1 = mild thickness; 2 = moderate thickness; 3 = severe thickness with inability to pinch the skin into a fold) for each of 17 surface anatomic areas of the body: face, anterior chest, abdomen, and, with right and left sides of the body separately evaluated, the fingers, forearms, upper arms, thighs, lower legs, dorsum of hands and feet. Individual values are summed and defined as the total skin score. Total score is 0 to 51 with higher scores indicating worse symptomology |
| %FVC Change From Baseline | End of treatment (Week 12) | Percent predicted FVC is calculated using equations incorporating age, gender, and race. It is calculated as (FVC Observed / FVC predicted) x 100, where FVC predicted is calculated relative to a reference population |
| Physician Global Assessment Change From Baseline | End of treatment (Week 12) | The physician's assessment of the patient's SSc status will be scored on a 100-mm horizontal VAS, ranging from 0 on the extreme left end of the scale indicating no disease activity (symptom free), and 100 on the extreme right end indicating worst imaginable disease activity. |
| Patient Global Assessment Change From Baseline | End of treatment (Week 12) | The Patient's Global Assessment represents the patient's overall assessment of current SSc status on a 100-mm horizontal VAS, ranging from 0 on the extreme left end of the scale indicating no disease activity (symptom free), and 100 on the extreme right end indicating worst imaginable disease activity. |
| Scleroderma HAQ-DI Change From Baseline | End of treatment (Week 12) | The HAQ-DI consists of 20 questions referring to eight component sets consisting of dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Each item is scored from 0 to 3. The eight scores of the eight sections are summed and divided by 8. The total score indicates the patient's self-assessed level of disability - higher scores indicate worse symptomology. A negative change from baseline indicates improvement. The Scleroderma HAQ (SHAQ) includes an additional five scleroderma-specific visual analogue scales (VAS), addressing overall disease activity, Raynaud's phenomenon, finger ulcers, breathing, and intestinal problems. A composite VAS score is not created nor are the individual VAS scores incorporated into the HAQ DI score. |
| Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) at Week 12 | Week 12 | CRISS components include modified Rodnan skin score (mRSS), forced vital capacity percent predicted (%FVC), Physician Global Assessment, Patient Global Assessment, and Health Assessment Questionnaire Disability-Index (HAQ-DI). The exponential algorithm determines the predicted probability of improvement from baseline, incorporating change in these 5 components. The outcome is a continuous variable between 0.0 and 1.0 (0 - 100%). A higher score indicates greater improvement |
| Scleroderma Clinical Trial Consortium Damage Index (SCTC-DI) Change From Baseline | End of treatment (Week 12) | The SCTC-DI is a 23-item composite damage index to quantify organ damage in systemic sclerosis (0-55 scale; moderate damage \>5, severe damage\>12) |
| 5-D Itch Scale Change From Baseline | End of treatment (Week 12) | The 5-D itch scale is a 23-item validated instrument used to measure five domains of chronic itch: duration, degree, direction, disability, and distribution. Scores range from 5 to 25, with higher scores indicating a higher severity of chronic itch. |
Countries
Australia, Netherlands, Poland, Spain, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FT011 200mg 200mg once daily for 12 weeks
FT011: Two x 100mg capsules once daily for 12 weeks | 10 |
| FT011 400mg 400mg once daily for 12 weeks
FT011: Two x 200mg capsules once daily for 12 weeks | 10 |
| Placebo Placebo once daily for 12 weeks
Placebo: Two placebo capsules once daily for 12 weeks | 10 |
| Total | 30 |
Baseline characteristics
| Characteristic | FT011 200mg | FT011 400mg | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 8 Participants | 9 Participants | 26 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 10 Participants | 10 Participants | 30 Participants |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 6 Participants | 22 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 7 / 10 | 4 / 10 | 6 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
FT011 Levels in Plasma
Measurement of maximum concentration (cmax) of FT011. First dose Cmax and last dose Cmax for each participant were averaged together to calculate a single mean Cmax for each treatment arm
Time frame: Mean of cmax post first dose and cmax post last dose
Population: Placebo participants not tested
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FT011 200mg | FT011 Levels in Plasma | 5.45 ug/mL | Standard Deviation 1.94 |
| FT011 400mg | FT011 Levels in Plasma | 10.3 ug/mL | Standard Deviation 4.27 |
Primary
FT011 Levels in Plasma
Measurement of time to cmax (tmax). First dose tmax and last dose tmax for each participant were averaged together to calculate a single mean tmax for each treatment arm
Time frame: Mean of time to cmax post first dose and time to cmax post last dose
Population: Placebo participants not tested
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FT011 200mg | FT011 Levels in Plasma | 4.19 hours | Standard Deviation 1.75 |
| FT011 400mg | FT011 Levels in Plasma | 4.20 hours | Standard Deviation 1.61 |
Primary
FT011 Levels in Plasma
Measurement of area under the concentration time curve (AUC). First dose AUC and last dose AUC for each participant were averaged together to calculate a single mean AUC for each active arm
Time frame: Mean of AUC hours post first dose and AUC hours post last dose
Population: Placebo participants not tested
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FT011 200mg | FT011 Levels in Plasma | 29.8 h*ug/mL | Standard Deviation 11.1 |
| FT011 400mg | FT011 Levels in Plasma | 57.8 h*ug/mL | Standard Deviation 29 |
Secondary
5-D Itch Scale Change From Baseline
The 5-D itch scale is a 23-item validated instrument used to measure five domains of chronic itch: duration, degree, direction, disability, and distribution. Scores range from 5 to 25, with higher scores indicating a higher severity of chronic itch.
Time frame: End of treatment (Week 12)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FT011 200mg | 5-D Itch Scale Change From Baseline | 0.7 score on a scale | Standard Deviation 2.55 |
| FT011 400mg | 5-D Itch Scale Change From Baseline | -0.7 score on a scale | Standard Deviation 4.47 |
| Placebo | 5-D Itch Scale Change From Baseline | 0.2 score on a scale | Standard Deviation 3.42 |
Secondary
Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) at Week 12
CRISS components include modified Rodnan skin score (mRSS), forced vital capacity percent predicted (%FVC), Physician Global Assessment, Patient Global Assessment, and Health Assessment Questionnaire Disability-Index (HAQ-DI). The exponential algorithm determines the predicted probability of improvement from baseline, incorporating change in these 5 components. The outcome is a continuous variable between 0.0 and 1.0 (0 - 100%). A higher score indicates greater improvement
Time frame: Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FT011 200mg | Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) at Week 12 | 0.282 score on a scale | Standard Deviation 0.4073 |
| FT011 400mg | Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) at Week 12 | 0.542 score on a scale | Standard Deviation 0.4535 |
| Placebo | Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) at Week 12 | 0.131 score on a scale | Standard Deviation 0.2397 |
Secondary
%FVC Change From Baseline
Percent predicted FVC is calculated using equations incorporating age, gender, and race. It is calculated as (FVC Observed / FVC predicted) x 100, where FVC predicted is calculated relative to a reference population
Time frame: End of treatment (Week 12)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FT011 200mg | %FVC Change From Baseline | -2 percentage of FVC change | Standard Deviation 2.24 |
| FT011 400mg | %FVC Change From Baseline | 4.7 percentage of FVC change | Standard Deviation 8.68 |
| Placebo | %FVC Change From Baseline | -1.7 percentage of FVC change | Standard Deviation 4.24 |
Secondary
mRSS Change From Baseline
The mRSS is a validated physical evaluation of patient's skin thickness rated by clinical palpation using a 0-3 scale (0 = normal skin; 1 = mild thickness; 2 = moderate thickness; 3 = severe thickness with inability to pinch the skin into a fold) for each of 17 surface anatomic areas of the body: face, anterior chest, abdomen, and, with right and left sides of the body separately evaluated, the fingers, forearms, upper arms, thighs, lower legs, dorsum of hands and feet. Individual values are summed and defined as the total skin score. Total score is 0 to 51 with higher scores indicating worse symptomology
Time frame: End of treatment (week 12)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FT011 200mg | mRSS Change From Baseline | -3.7 score on a scale | Standard Deviation 4.3 |
| FT011 400mg | mRSS Change From Baseline | -3.1 score on a scale | Standard Deviation 4.15 |
| Placebo | mRSS Change From Baseline | -2.7 score on a scale | Standard Deviation 3.53 |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) From Baseline to End of Study
TEAEs per arm during study treatment and follow up periods
Time frame: Baseline to Week 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FT011 200mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) From Baseline to End of Study | 7 Participants |
| FT011 400mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) From Baseline to End of Study | 4 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) From Baseline to End of Study | 6 Participants |
Secondary
Patient Global Assessment Change From Baseline
The Patient's Global Assessment represents the patient's overall assessment of current SSc status on a 100-mm horizontal VAS, ranging from 0 on the extreme left end of the scale indicating no disease activity (symptom free), and 100 on the extreme right end indicating worst imaginable disease activity.
Time frame: End of treatment (Week 12)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FT011 200mg | Patient Global Assessment Change From Baseline | 23 score on a scale | Standard Deviation 9.53 |
| FT011 400mg | Patient Global Assessment Change From Baseline | 10.8 score on a scale | Standard Deviation 30.07 |
| Placebo | Patient Global Assessment Change From Baseline | 2.7 score on a scale | Standard Deviation 19.99 |
Secondary
Physician Global Assessment Change From Baseline
The physician's assessment of the patient's SSc status will be scored on a 100-mm horizontal VAS, ranging from 0 on the extreme left end of the scale indicating no disease activity (symptom free), and 100 on the extreme right end indicating worst imaginable disease activity.
Time frame: End of treatment (Week 12)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FT011 200mg | Physician Global Assessment Change From Baseline | -15.2 score on a scale | Standard Deviation 19.78 |
| FT011 400mg | Physician Global Assessment Change From Baseline | -28.4 score on a scale | Standard Deviation 22.89 |
| Placebo | Physician Global Assessment Change From Baseline | -6.3 score on a scale | Standard Deviation 18.29 |
Secondary
Scleroderma Clinical Trial Consortium Damage Index (SCTC-DI) Change From Baseline
The SCTC-DI is a 23-item composite damage index to quantify organ damage in systemic sclerosis (0-55 scale; moderate damage \>5, severe damage\>12)
Time frame: End of treatment (Week 12)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FT011 200mg | Scleroderma Clinical Trial Consortium Damage Index (SCTC-DI) Change From Baseline | -0.3 score on a scale | Standard Deviation 0.71 |
| FT011 400mg | Scleroderma Clinical Trial Consortium Damage Index (SCTC-DI) Change From Baseline | -0.3 score on a scale | Standard Deviation 0.95 |
| Placebo | Scleroderma Clinical Trial Consortium Damage Index (SCTC-DI) Change From Baseline | -1.2 score on a scale | Standard Deviation 2.54 |
Secondary
Scleroderma HAQ-DI Change From Baseline
The HAQ-DI consists of 20 questions referring to eight component sets consisting of dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Each item is scored from 0 to 3. The eight scores of the eight sections are summed and divided by 8. The total score indicates the patient's self-assessed level of disability - higher scores indicate worse symptomology. A negative change from baseline indicates improvement. The Scleroderma HAQ (SHAQ) includes an additional five scleroderma-specific visual analogue scales (VAS), addressing overall disease activity, Raynaud's phenomenon, finger ulcers, breathing, and intestinal problems. A composite VAS score is not created nor are the individual VAS scores incorporated into the HAQ DI score.
Time frame: End of treatment (Week 12)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FT011 200mg | Scleroderma HAQ-DI Change From Baseline | -0.0694 score on a scale | Standard Deviation 0.26598 |
| FT011 400mg | Scleroderma HAQ-DI Change From Baseline | -0.2625 score on a scale | Standard Deviation 0.23162 |
| Placebo | Scleroderma HAQ-DI Change From Baseline | 0.0278 score on a scale | Standard Deviation 0.24826 |