COVID-19 Disease
Conditions
Keywords
COVID-19, SARS-CoV-2, Apilimod Dimesylate, LAM-002A, Coronavirus, AI Therapeutics
Brief summary
This is a clinical trial to evaluate the efficacy of LAM-002A compared to placebo treatment in adults with a confirmed SARS-CoV-2 infection who are receiving standards supportive care in an outpatient setting.
Detailed description
This is a Phase II randomized, double-blind, placebo-controlled, clinical study to evaluate the efficacy of LAM-002A compared to placebo treatment in adults with a confirmed SARS-CoV-2 infection who are receiving standard supportive care in an outpatient setting. Study eligibility will be assessed during screening. All study participants must sign a written informed consent and satisfy the inclusion and exclusion criteria for the study. Confirmation of SARS-CoV-2 infection, medical history, and current medication will be assessed for each consenting participant at screening. Study participants will be randomized in a 1:1 ratio, to receive study therapy (either LAM-002A, 125 mg \[5 capsules/dose\]) PO BID or placebo \[5 capsules/dose\] PO BID) for 10 days. Participants who experience an adverse event (AE) considered to be related to study therapy may have a decrease in study dose of LAM-002A to 100 mg \[4 capsules/dose\]) PO BID or placebo \[4 capsules/dose\] PO BID). After the start of treatment on Day 1, participants will be followed at Days 4,6,8,11,22, and 28. Days 6,8, and 22 will be phone visits. Participants can withdraw from the study therapy or study participation at any time. The study will incorporate an interim safety analysis after the first 30 participants (15 on LAM-002A and 15 on placebo) have completed treatment and have been followed up for 11 days post-first dose. Recruitment and randomization will continue while this analysis is conducted. Recommendations from an independent Data Safety Monitoring Board (DSMB) will be used for decisions of early termination or study design adaptations. Non-parametric and parametric statistical analysis will be conducted, as appropriate. For the comparison of the LAM-002A active arm and the control arm for the primary endpoint and secondary endpoints of drug effect, appropriate methods will be employed. Baseline subject characteristics, study therapy administration/compliance, safety, supportive care administration, and pharmacokinetics will be analyzed descriptively.
Interventions
DRUGApilimod Dimesylate Capsule
LAM-002A is formulated in capsules containing 25 mg of apilimod dimesylate. The capsule is Swedish orange, Size 0.
OTHERPlacebo
Microcrystalline cellulose in Swedish orange, Size 0 capsules
Sponsors
Yale University
OrphAI Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blinded
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written documentation of SARS-CoV-2 infection confirmed by a validated test. 2. Presence of greater than or equal to ≥1 of the following COVID-19-related symptoms indicating mild disease: fever (temperature ≥100.4), anosmia (loss of taste or smell), cough, sore throat, gastrointestinal complaints (e.g. nausea, vomiting, or diarrhea), chills, congestion, or runny nose, headaches, muscle or body aches, fatigue, or asymptomatic patients who have tested positive for COVID-19 via a validated test within the past 4 days. 3. If symptomatic, symptom onset less than or equal to ≤ 8 days. 4. For female participants of childbearing potential, a negative urine (or serum) pregnancy test. 5. For female participants of childbearing potential, willingness to use a protocol-recommended method of contraception from the start of the screening period until greater than or equal to ≥30 days after the final dose of study therapy. Note: A female subject is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle-stimulating hormone \[FSH\] levels within the institutional laboratory postmenopausal range and a negative serum or urine beta human chorionic gonadotropin \[βHCG\]); or is menopausal (age ≥50 years with amenorrhea for ≥6 months). 6. For male participants who can father a child and are having intercourse with females of childbearing potential who are not using adequate contraception, willingness to use a protocol-recommended method of contraception from the start of study therapy until ≥30 days after the final dose of study therapy and to refrain from sperm donation from the start of study therapy until ≥90 days after administration of the final dose of study therapy. Note: A male subject is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy. 7. Willingness and ability of the participant to ingest study drug capsules. 8. Willingness of the participant to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, study procedures, and study restrictions. 9. Evidence of a personally signed informed consent indicating that the participant is aware of the nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation.
Exclusion criteria
1. Respiratory rate greater than or equal to ≥20 breaths per minute. 2. Oxygen saturation by pulse oximetry less than or equal to ≤93 percent % on room air or requirement for supplemental oxygen to maintain oxygen saturation greater than \>93 percent %. 3. Total NEWS score greater than or equal to ≥6 or presence of a score of 3 on any of the individual NEWS parameters. 4. Radiographic evidence of pulmonary infiltrates (clinical X-ray within 2 days of referral) 5. Hepatic profile showing any of the following: * Serum alanine aminotransferase (ALT) greater than \>5 × upper limit of normal (ULN) (CTCAE Grade greater than or equal to ≥3). * Serum aspartate aminotransferase (AST) greater than \>5 × ULN (CTCAE Grade greater than or equal to ≥3). * Serum bilirubin greater than \>1.5 × ULN (CTCAE Grade greater than or equal to ≥2). 6. Renal profile showing an estimated creatinine clearance (eClCR) less than \<30 mL/minute (with eClCR to be calculated by the method at the laboratory performing the serum creatinine test). 7. Presence of a cancer with disease manifestations or therapy that could adversely affect subject safety or longevity, create the potential for drug-drug interactions, or compromise the interpretation of study results. 8. Significant cardiovascular disease (e.g. myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 1 month prior to start of study therapy; unstable angina; symptomatic peripheral vascular disease; CTCAE Grade greater than or equal to ≥2 congestive heart failure; or uncontrolled CTCAE Grade greater than or equal to ≥3 hypertension (diastolic blood pressure greater than or equal to ≥100 mmHg or systolic blood pressure greater than or equal to ≥160 mmHg) despite antihypertensive therapy. 9. Significant screening ECG abnormalities, including atrial fibrillation/flutter, 2nd degree atrioventricular (AV) block type II, 3rd-degree AV block, Grade greater than or equal to ≥2 bradycardia, or corrected QT (QTc by Fridericia \[QTcF\]) greater than \>480 msec (Grade greater than \>1). 10. Gastrointestinal disease (e.g. gastric or intestinal bypass surgery, pancreatic enzyme insufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease, chronic diarrheal illness, bowel obstruction) that might interfere with drug absorption or with interpretation of gastrointestinal AEs. 11. Pregnancy or breastfeeding. 12. Prior solid organ transplantation. 13. Use within 5 days prior to randomization of an approved or investigational therapy intended to treat COVID-19 (e.g. remdesivir, , anti-interleukin \[IL\]-6 antibodies, therapeutic anti-SARS CoV-2 antibodies or post-convalescent plasma, anti- SARS CoV-2 vaccine, Bruton tyrosine kinase \[BTK\] inhibitor), use within 3 months of chloroquine or hydroxychloroquine. Note: participants are not precluded from undergoing evaluations involving observation, noninvasive diagnostic procedures or sampling, or questionnaires as follow-up to a prior study or as components of a concurrent noninterventional study. 14. Use within 5 days prior to randomization of a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 or expected requirement for chronic use of a strong inhibitor or inducer of CYP3A4 during study therapy. 15. Use within 5 days prior to randomization of drug that is a moderate-to-strong substrate of CYP2C9 (including warfarin, tolbutamide, phenytoin, glimepiride) or expected requirement for chronic use of such drugs during study therapy. 16. Use within 5 days prior to randomization of a drug known to prolong the QT interval 17. Ongoing immunosuppressive therapy including systemic or enteric corticosteroids. (Note: At study entry, participants may be using intraarticular, inhaled, or topical corticosteroids. During study therapy, participants may use systemic, enteric, intraarticular, inhaled, or topical corticosteroids as required for intercurrent conditions.) 18. Any illness, medical condition, organ system dysfunction, or social situation, including mental illness or substance abuse, deemed by the investigator to be likely to interfere with a participant's ability to provide informed consent, adversely affect the participant's ability to cooperate and participate in the study, or compromise the interpretation of study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Viral Load Change | 4 Days | The primary efficacy outcome measure evaluated change in SARS-CoV-2 viral load at Day 4 from Day 1, of LAM-002A or placebo-treated participants. SARS-CoV-2 viral load was measured by a real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) test of nasopharyngeal samples. Analysis focused on log10 viral load on Day 4 compared to baseline viral load at Day 1 in participants with baseline viral load \>100,000 copies/mL |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 28 Days | The number and percentage of LAM 002A-treated participants who developed TEAEs compared to placebo |
| Clinical Efficacy | 28 Days | Number of Participants with Hospitalization or Death within 28 days |
| Change in COVID-19 Clinical Status | 28 Days | To evaluate change in COVID-19 clinical status, as defined by the ordinal scale, of participants treated with LAM-002A compared to placebo at Day 28, in participants who became hospitalized and continued LAM-002A/placebo treatment, based on the following scores: 1. Not in the hospital 2. Hospitalized, requiring low flow supplemental oxygen (such as nasal cannula) 3. Hospitalized, not on invasive ventilation (such as 100% non-rebreather, BIPAP), (pre-ICU) 4. Hospitalized, in the ICU, on invasive ventilation or Extracorporeal membrane oxygenation (ECMO) 5. Dead |
| Oxygen Saturation | Baseline, Day 1, Day 4, Day 11, Day28 | Comparison of the number and percentage of participants with an oxygen saturation (O2 sat) ≥95% between LAM-002A versus placebo treatment groups. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Participants With Viral Load < Lower Limit of Quantification (LLOQ) | 4 Days | Evaluated the difference in the number and percentage of participants with a SARS-CoV-2 viral load \<LLOQ between the LAM-002A and the placebo arm as measured by a qRT-PCR test from nasopharyngeal samples at Day 4. |
Countries
United States
Participant flow
Recruitment details
This study was conducted by 8 investigators located at medical centers throughout the United States
Pre-assignment details
The screening and baseline visits could occur on the same day. Day 1 of the study was the day the participant took the first dose of study drug after randomization.
Participants by arm
| Arm | Count |
|---|---|
| LAM-002A 71 subjects were allocated to receive LAM-002A (Apilimod Dimesylate) 125 mg in five 25-mg capsules BID for 10 days. | 71 |
| Placebo 71 subjects were allocated to receive Placebo (microcrystalline cellulose) in 5 capsules BID for 10 days. | 71 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Not eligible | 0 | 1 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo | LAM-002A |
|---|---|---|---|
| Age, Continuous | 43.1 years | 43.3 years | 42.8 years |
| ECOG Performance Status 0: Fully active | 114 Participants | 59 Participants | 55 Participants |
| ECOG Performance Status 1: Restricted | 27 Participants | 11 Participants | 16 Participants |
| ECOG Performance Status 2: Ambulatory | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 52 Participants | 27 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 89 Participants | 44 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Oxygen Saturation | 98.0 percent | 98.0 percent | 98.0 percent |
| Race/Ethnicity, Customized Patient Race Asian | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Patient Race Black or African American | 9 Participants | 7 Participants | 2 Participants |
| Race/Ethnicity, Customized Patient Race Other | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Patient Race Unknown | 4 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Patient Race White | 125 Participants | 61 Participants | 64 Participants |
| Region of Enrollment United States | 142 participants | 71 participants | 71 participants |
| Sex: Female, Male Female | 74 Participants | 37 Participants | 37 Participants |
| Sex: Female, Male Male | 68 Participants | 34 Participants | 34 Participants |
| Temperature | 36.8 degrees Celsius | 36.8 degrees Celsius | 36.8 degrees Celsius |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 71 | 0 / 70 |
| other Total, other adverse events | 26 / 71 | 15 / 70 |
| serious Total, serious adverse events | 2 / 71 | 1 / 70 |
Outcome results
Primary
Viral Load Change
The primary efficacy outcome measure evaluated change in SARS-CoV-2 viral load at Day 4 from Day 1, of LAM-002A or placebo-treated participants. SARS-CoV-2 viral load was measured by a real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) test of nasopharyngeal samples. Analysis focused on log10 viral load on Day 4 compared to baseline viral load at Day 1 in participants with baseline viral load \>100,000 copies/mL
Time frame: 4 Days
Population: Antiviral efficacy population comprising of participants with baseline viral load \>100,000 copies/mL = log10 viral load \>5)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAM-002A | Viral Load Change | -2.50 log10 copies/mL | Standard Deviation 2.35 |
| Placebo | Viral Load Change | -1.99 log10 copies/mL | Standard Deviation 1.71 |
Comparison: The analysis tested whether the viral load in nasopharyngeal samples was lower at Day 4 in those receiving LAM-002A compared to Placebo.p-value: 0.3595% CI: [-1.47, 0.53]Mixed Models Analysis
Secondary
Change in COVID-19 Clinical Status
To evaluate change in COVID-19 clinical status, as defined by the ordinal scale, of participants treated with LAM-002A compared to placebo at Day 28, in participants who became hospitalized and continued LAM-002A/placebo treatment, based on the following scores: 1. Not in the hospital 2. Hospitalized, requiring low flow supplemental oxygen (such as nasal cannula) 3. Hospitalized, not on invasive ventilation (such as 100% non-rebreather, BIPAP), (pre-ICU) 4. Hospitalized, in the ICU, on invasive ventilation or Extracorporeal membrane oxygenation (ECMO) 5. Dead
Time frame: 28 Days
Population: The intention-to-treat (ITT) population included all participants randomized according to their initial randomized assignment regardless of the treatment actually received.~\* Participant 008-109 in the LAM-002A group was in the hospital at Day 28, but her score is missing, this participant died in the hospital on Day 30.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LAM-002A | Change in COVID-19 Clinical Status | 1: Not in the hospital | 64 Participants |
| LAM-002A | Change in COVID-19 Clinical Status | 2: Hospitalized, requiring low flow supplemental oxygen (such as nasal cannula) | 0 Participants |
| LAM-002A | Change in COVID-19 Clinical Status | 3: Hospitalized, not on invasive ventilation (such as 100% non-rebreather, BIPAP), (pre-ICU) | 0 Participants |
| LAM-002A | Change in COVID-19 Clinical Status | 4: Hospitalized, in the ICU, on invasive ventilation or ECMO | 0 Participants |
| LAM-002A | Change in COVID-19 Clinical Status | 5: Dead | 0 Participants |
| LAM-002A | Change in COVID-19 Clinical Status | Status Unknown* | 7 Participants |
| Placebo | Change in COVID-19 Clinical Status | 5: Dead | 0 Participants |
| Placebo | Change in COVID-19 Clinical Status | 1: Not in the hospital | 66 Participants |
| Placebo | Change in COVID-19 Clinical Status | 4: Hospitalized, in the ICU, on invasive ventilation or ECMO | 0 Participants |
| Placebo | Change in COVID-19 Clinical Status | 2: Hospitalized, requiring low flow supplemental oxygen (such as nasal cannula) | 0 Participants |
| Placebo | Change in COVID-19 Clinical Status | Status Unknown* | 5 Participants |
| Placebo | Change in COVID-19 Clinical Status | 3: Hospitalized, not on invasive ventilation (such as 100% non-rebreather, BIPAP), (pre-ICU) | 0 Participants |
Secondary
Clinical Efficacy
Number of Participants with Hospitalization or Death within 28 days
Time frame: 28 Days
Population: The intention-to-treat (ITT) population included all participants randomized according to their initial randomized assignment regardless of the treatment actually received.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LAM-002A | Clinical Efficacy | Yes | 2 Participants |
| LAM-002A | Clinical Efficacy | No | 69 Participants |
| Placebo | Clinical Efficacy | Yes | 1 Participants |
| Placebo | Clinical Efficacy | No | 70 Participants |
p-value: 0.5595% CI: [0.18, 22.89]Log Rank
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
The number and percentage of LAM 002A-treated participants who developed TEAEs compared to placebo
Time frame: 28 Days
Population: All participants who received at least 1 dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LAM-002A | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 26 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 14 Participants |
Secondary
Oxygen Saturation
Comparison of the number and percentage of participants with an oxygen saturation (O2 sat) ≥95% between LAM-002A versus placebo treatment groups.
Time frame: Baseline, Day 1, Day 4, Day 11, Day28
Population: The intention-to-treat (ITT) population included all participants randomized according to their initial randomized assignment regardless of the treatment actually received.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| LAM-002A | Oxygen Saturation | Baseline, oxygen saturation ≥95% | Yes | 67 Participants |
| LAM-002A | Oxygen Saturation | Baseline, oxygen saturation ≥95% | No | 4 Participants |
| LAM-002A | Oxygen Saturation | Day 1, oxygen saturation ≥95% | Yes | 60 Participants |
| LAM-002A | Oxygen Saturation | Day 1, oxygen saturation ≥95% | No | 2 Participants |
| LAM-002A | Oxygen Saturation | Day 4, oxygen saturation ≥95% | Yes | 59 Participants |
| LAM-002A | Oxygen Saturation | Day 4, oxygen saturation ≥95% | No | 9 Participants |
| LAM-002A | Oxygen Saturation | Day 11, oxygen saturation ≥95% | Yes | 60 Participants |
| LAM-002A | Oxygen Saturation | Day 11, oxygen saturation ≥95% | No | 4 Participants |
| LAM-002A | Oxygen Saturation | Day 28, oxygen saturation ≥95% | Yes | 65 Participants |
| LAM-002A | Oxygen Saturation | Day 28, oxygen saturation ≥95% | No | 0 Participants |
| Placebo | Oxygen Saturation | Day 11, oxygen saturation ≥95% | No | 2 Participants |
| Placebo | Oxygen Saturation | Baseline, oxygen saturation ≥95% | Yes | 68 Participants |
| Placebo | Oxygen Saturation | Day 4, oxygen saturation ≥95% | No | 3 Participants |
| Placebo | Oxygen Saturation | Baseline, oxygen saturation ≥95% | No | 3 Participants |
| Placebo | Oxygen Saturation | Day 28, oxygen saturation ≥95% | No | 0 Participants |
| Placebo | Oxygen Saturation | Day 1, oxygen saturation ≥95% | Yes | 59 Participants |
| Placebo | Oxygen Saturation | Day 11, oxygen saturation ≥95% | Yes | 65 Participants |
| Placebo | Oxygen Saturation | Day 1, oxygen saturation ≥95% | No | 2 Participants |
| Placebo | Oxygen Saturation | Day 28, oxygen saturation ≥95% | Yes | 66 Participants |
| Placebo | Oxygen Saturation | Day 4, oxygen saturation ≥95% | Yes | 65 Participants |
Comparison: Risk Difference from generalized estimating equations (GEE) logistic regression at Baseline
Comparison: Risk Difference from GEE Logistic Regression at Day 1
Comparison: Risk Difference from GEE logistic regression at Day 4
Comparison: Risk Difference from GEE logistic regression at Day 11
Other Pre-specified
Number and Percentage of Participants With Viral Load < Lower Limit of Quantification (LLOQ)
Evaluated the difference in the number and percentage of participants with a SARS-CoV-2 viral load \<LLOQ between the LAM-002A and the placebo arm as measured by a qRT-PCR test from nasopharyngeal samples at Day 4.
Time frame: 4 Days
Population: Antiviral efficacy population comprising participants with baseline viral load \>100,000 copies/ml = log10 viral load \>5)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LAM-002A | Number and Percentage of Participants With Viral Load < Lower Limit of Quantification (LLOQ) | 9 Participants |
| Placebo | Number and Percentage of Participants With Viral Load < Lower Limit of Quantification (LLOQ) | 3 Participants |
p-value: 0.295% CI: [0.74, 8.48]Fisher Exact