Safety, Pharmacokinetics, and Efficacy of Subcutaneous Isatuximab in Adults With Warm Autoimmune Hemolytic Anemia (wAIHA)
- Conditions
- Warm Autoimmune Hemolytic Anemia (wAIHA)
- Interventions
- Registration Number
- NCT04661033
- Lead Sponsor
- Sanofi
- Brief Summary
Primary Objectives:
* Part A: To evaluate the safety and tolerability of subcutaneous injections of isatuximab in adults with wAIHA
* Part B: To evaluate the efficacy of the selected dose in adults with wAIHA
Secondary Objectives:
* Part A (Cohorts 2 and 3 only)
* To evaluate the efficacy of isatuximab in adults with wAIHA
* To evaluate the durability of response to isatuximab and time to response
* To evaluate the impact of isatuximab treatment on fatigue
Part B
* To evaluate the safety and tolerability of isatuximab in adults with wAIHA
* To evaluate the durability of response to isatuximab and time to response
* To evaluate the impact of isatuximab treatment on fatigue
Parts A (all Cohorts) and B
* To evaluate the effect of isatuximab on markers of hemolysis
* To characterize the pharmacokinetic profile of isatuximab in adults with wAIHA
* To evaluate the immunogenicity of isatuximab
- Detailed Description
28 weeks (including screening)
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 8
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part A: Cohort 1: Isatuximab 140 mg SC Q2W x2 Isatuximab SAR650984 Participants received 2 doses of Isatuximab 140 milligrams (mg) (1 milliliter \[mL\]) via subcutaneous (SC) injection every 2 weeks (Q2W) on Day 1 and Day 15. Part A: Cohort 2: Isatuximab 280 mg SC Q2W x6 Isatuximab SAR650984 Participants received 6 doses of Isatuximab 280 mg (2 mL) via SC injection Q2W through Day 71. Part A: Cohort 3: Isatuximab 560 mg SC Q2W x6 Isatuximab SAR650984 Participants received 6 doses of Isatuximab 560 mg (4 mL) via SC injection Q2W through Day 71. Part B: Isatuximab up to 560 mg SC Q2W x6 Isatuximab SAR650984 Participants were planned to receive 6 doses of Isatuximab up to 560 mg (4 mL) via SC injection Q2W through Day 71
- Primary Outcome Measures
Name Time Method Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) And Treatment Emergent Serious Adverse Events (TESAEs) From first dose of study drug (Day 1) up to 30 days after last study intervention administration, approximately 101 days An adverse event (AE) is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAE is defined as an AE that occurred from the time of the first IMP administration up to 30 days (included) after the last IMP administration. A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, was a medically important event.
Part A: Number of Participants With Potentially Clinically Significant Abnormality (PCSA): Hematology From first dose of study drug (Day 1) up to end of study, approximately 169 days Blood samples were collected to determine the hematology laboratory significant abnormalities. PCSA values: abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: Hemoglobin (Hb): ≤ 115 grams per Liter (g/L) (Male\[M\]); ≤ 95 g/L (Female\[F\]), ≥ 185 g/L (M); ≥ 165 g/L (F), Decrease from baseline ≥ 20 g/L; Hematocrit: ≤ 0.37 volume per volume (v/v) (M); ≤ 0.32 v/v (F), ≥ 0.55 v/v (M); ≥ 0.5 v/v (F); Erythrocyte Count: ≥ 6 x 10\^12 per Liter (/L); Platelet count: \< 100 x 10\^9/L, ≥ 700 x 10\^9/L; Leukocytes: \< 3 x 10\^9/L (Non-Black \[NB\]); \< 2 x 10\^9/L (Black \[B\]), ≥ 16 x 10\^9/L; Neutrophils: \< 1.5 x 10\^9/L (B); \< 1 x 10\^9/L (B); Lymphocytes: \> 4 x 10\^9/L; Monocytes: \> 0.7 x 10\^9/L; Basophils: \> 0.1 x 10\^9/L; Eosinophils: \> 0.5 x 10\^9/L or \> Upper limit of Normal (ULN) (if ULN ≥ 0.5 x 10\^9/L).
Part A: Number of Participants With PCSA: Clinical Chemistry And Electrolyte Parameters From first dose of study drug (Day 1) up to end of study, approximately 169 days Blood samples were collected to determine the clinical chemistry laboratory and electrolyte parameters significant abnormalities. PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: Glucose: ≤ 3.9 millimoles per Liter (mmol/L) and \< Lower limit of normal (LLN), ≥ 11.1 mmol/L (unfasted); ≥ 7 mmol/L (fasted); Creatinine: ≥ 150 micromoles (µmol)/L, ≥ 30% change from baseline, ≥ 100% change from baseline, Alanine Aminotransferase (ALT): \> 3 ULN, \> 5 ULN, \> 10 ULN; Aspartate Aminotransferase (AST): \> 3 ULN; Alkaline Phosphatase (ALP): \> 1.5 ULN; Total Bilirubin: \> 1.5 ULN, \> 2 ULN; Sodium: ≤ 129 mmol/L, ≥ 160 mmol/L and Potassium: \< 3 mmol/L, ≥ 5.5 mmol/L.
Part B: Overall Response Rate (Response [R] Or Complete Response [CR]) At Day 85 Day 85 Overall response rate was defined as the percentage of participants with a response (R) or complete response (CR) over the evaluable participants. R was defined as an increase in Hb by ≥2 g/dL from baseline and an absence of transfusion in the last 7 days and absence of rescue medications in the past 4 weeks. Biochemical evidence of hemolysis might still be present. CR was defined as Hb ≥11 g/dL (women) or ≥12 g/dL (men), no evidence of hemolysis (normal bilirubin, Lactate dehydrogenase \[LDH\], haptoglobin, and reticulocytes), and absence of transfusion in the last 7 days and absence of rescue medication in the past 4 weeks.
Part A: Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs From first dose of study drug (Day 1) up to end of study, approximately 169 days Vital signs were examined to determine the abnormalities. Vital signs included Sitting systolic blood pressure (SSBP), Sitting diastolic blood pressure (SDBP), Sitting heart rate (SHR) and weight. PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: SSBP: ≤95 millimeters of mercury (mmHg) and decrease from baseline ≥20 mmHg; ≥160 mmHg and increase from baseline ≥20 mmHg; SDBP: ≤45 mmHg and decrease from baseline ≥10 mmHg, ≥ 110 mmHg and increase from baseline ≥ 10 mmHg; SHR: ≤ 50 beats per minute (bpm) and decrease from baseline ≥ 20 bpm, ≥120 bpm and increase from baseline ≥ 20 bpm; Weight: ≥ 5% decrease from baseline, ≥5% increase from baseline.
Part A: Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis From first dose of study drug (Day 1) up to end of study, approximately 169 days Urine samples were collected to determine the urinalysis parameter significant abnormalities. PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: pH: ≤ 4.6 or ≥ 8.
- Secondary Outcome Measures
Name Time Method Part A: Absolute Change From Baseline In Lactate Dehydrogenase (LDH) at 1, 2, 4, 8, 12, and 24 Weeks Cohort 1 : Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, and 12; Cohorts 2 and 3: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24 Blood samples were collected to evaluate the effect of Isatuximab on marker of hemolysis: LDH. Baseline is defined as the last assessment value before IMP.
Part A: Absolute Change From Baseline In Haptoglobin at 1, 2, 4, 8, 12, and 24 Weeks Cohort 1 : Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, and 12; Cohorts 2 and 3: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24 Blood samples were collected to evaluate the effect of Isatuximab on marker of hemolysis: Haptoglobin. Baseline was defined as the last assessment value before IMP.
Part A: Time to Reach Cmax (Tmax) of Isatuximab Post-dose on Day 1 Blood samples were collected at the specified timepoints. Tmax was defined as time to reach Cmax. The non-compartmental PK analysis was performed.
Part A: Area Under the Plasma Concentration Versus Time Curve Over the Dosing Interval (AUCtau) of Isatuximab Post-dose on Day 1 Blood samples were collected at the specified timepoints. AUCtau was defined as area under the plasma concentration versus time curve over the dosing interval. The non-compartmental PK analysis was performed.
Part B: Number of Participants With Potentially Clinically Significant Abnormality: Vital Signs From first dose of study drug (Day 1) up to end of study, approximately 169 days Vital signs were planned to be examined to determine the abnormalities. Vital signs included SSBP, SDBP, SHR and weight. PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: SSBP: ≤ 95 mmHg and decrease from baseline ≥ 20 mmHg, ≥ 160 mmHg and increase from baseline ≥20 mmHg; SDBP: ≤ 45 mmHg and decrease from baseline ≥ 10 mmHg, ≥ 110 mmHg and increase from baseline ≥ 10 mmHg; SHR: ≤ 50 bpm and decrease from baseline ≥ 20 bpm, ≥ 120 bpm and increase from baseline ≥ 20 bpm; Weight: ≥ 5% decrease from baseline, ≥5% increase from baseline.
Part B: Percentage Of Participants With Durable Hemoglobin Response By Day 169 From first dose of study drug (Day 1) up to end of study (Day 169) Durable response was defined as Hb level ≥10 g/dL with an increase from baseline of ≥2 g/dL on three consecutive evaluable visits during the study period; with absence of transfusion and no rescue medication during the period of 3 consecutive visits and for at least 7 days (transfusions) and 4 weeks (rescue medication) prior to the first consecutive visit.
Part B: Absolute Change From Baseline In FACIT-Fatigue Scale Score At Day 85 And Day 169 Baseline (Day 1) and Day 85 and Day 169 The FACIT-Fatigue scale is a 13-item questionnaire assessing fatigue where participants scored each item on a 5-point scale (0 to 4): 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much. To score the FACIT-fatigue, all items are summed to create a single fatigue score with a range from 0 to 52, where higher score (and positive change scores) indicated better functioning. Baseline was defined as the Day 1 pre-dose value.
Part A: Cohorts 2 and 3: Overall Response Rate (Response [R] Or Complete Response [CR]) At Day 85 And Day 169 Day 85 and Day 169 Overall response rate was defined as the percentage of participants with a R or CR over the evaluable participants. R was defined as an increase in Hb by ≥2 g/dL from baseline and an absence of transfusion in the last 7 days and absence of rescue medications in the past 4 weeks. Biochemical evidence of hemolysis might still be present. CR was defined as Hb ≥11 g/dL (women) or ≥12 g/dL (men), no evidence of hemolysis (normal bilirubin, LDH, haptoglobin, and reticulocytes), and absence of transfusion in the last 7 days and absence of rescue medication in the past 4 weeks
Part A: Cohorts 2 and 3: Percentage Of Participants With Durable Hemoglobin (Hb) Response By Day 169 From first dose of study drug (Day 1) up to end of study (Day 169) Durable response was defined as Hb level ≥10 g/dL with an increase from baseline of ≥2 g/dL on three consecutive evaluable visits during the study period; with absence of transfusion and no rescue medication during the period of 3 consecutive visits and for at least 7 days (transfusions) and 4 weeks (rescue medication) prior to the first consecutive visit.
Part A: Absolute Change From Baseline In Reticulocytes at 1, 2, 4, 8, 12, and 24 Weeks Cohort 1 : Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, and 12; Cohorts 2 and 3: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24 Blood samples were collected to evaluate the effect of Isatuximab on marker of hemolysis: Reticulocytes. Baseline was defined as the last assessment value before IMP.
Part A: Absolute Change From Baseline In Total Bilirubin at 1, 2, 4, 8, 12, and 24 Weeks Cohort 1 : Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, and 12; Cohorts 2 and 3: Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24 Blood samples were collected to evaluate the effect of Isatuximab on marker of hemolysis: Total Bilirubin. Baseline was defined as the last assessment value before IMP.
Part A: Maximum Observed Concentration (Cmax) Of Isatuximab Post-dose on Day 1 Blood samples were collected at the specified timepoints. Cmax was defined as maximum concentration observed after the first infusion. The non-compartmental pharmacokinetic (PK) analysis was performed.
Part B: Number of Participants With PCSA: Hematology From first dose of study drug (Day 1) up to end of study, approximately 169 days Blood samples were planned to be collected to determine the hematology laboratory significant abnormalities. PCSA values: abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: Hb: ≤ 115 g/L (M); ≤ 95 g/L (F), ≥ 185 g/L (M); ≥ 165 g/L (F), Decrease from baseline ≥ 20 g/L; Hematocrit: ≤ 0.37 v/v (M); ≤ 0.32 v/v (F), ≥ 0.55 v/v (M); ≥ 0.5 v/v (F); Erythrocyte Count: ≥ 6 x 10\^12/L); Platelet count: \< 100 x 10\^9/L, ≥ 700 x 10\^9/L; Leukocytes: \< 3 x 10\^9/L (NB); \< 2 x 10\^9/L (B), ≥ 16 x 10\^9/L; Neutrophils: \< 1.5 x 10\^9/L (B); \< 1 x 10\^9/L (B); Lymphocytes: \> 4 x 10\^9/L; Monocytes: \> 0.7 x 10\^9/L; Basophils: \> 0.1 x 10\^9/L; Eosinophils: \> 0.5 x 10\^9/L or \> ULN (if ULN ≥ 0.5 x 10\^9/L).
Part B: Absolute Change From Baseline In Reticulocytes at 1, 2, 4, 8, 12, and 24 Weeks Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24 Blood samples were planned to be collected to evaluate the effect of Isatuximab on marker of hemolysis: Reticulocytes. Baseline was defined as the last assessment value before IMP
Part B: Cmax Of Isatuximab Post-dose on Day 1 Blood samples were planned to be collected at the specified timepoints. Cmax was defined as maximum concentration observed after the first infusion.
Part B: AUCtau of Isatuximab Post-dose on Day 1 Blood samples were planned to be collected at the specified timepoints. AUCtau was defined as area under the plasma concentration versus time curve over the dosing interval.
Part B: Mean Plasma Trough Concentration Of Isatuximab Post-dose on Days 15, 29, 43 and 57 Blood samples were planned to be collected at the specified timepoints.
Part A: Cohorts 2 and 3: Absolute Change From Baseline in Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scale Score At Day 85 and Day 169 Baseline (Day 1), Day 85 and Day 169 The FACIT-Fatigue scale is a 13-item questionnaire assessing fatigue where participants scored each item on a 5-point scale (0 to 4): 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much. To score the FACIT-fatigue, all items are summed to create a single fatigue score with a range from 0 to 52, where higher score (and positive change scores) indicated better functioning. Baseline was defined as the Day 1 pre-dose value.
Part B: Number of Participants With Potentially Clinically Significant Abnormality: Urinalysis From first dose of study drug (Day 1) up to end of study, approximately 169 days Urine samples were planned to be collected to determine the urinalysis parameter significant abnormalities. PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: pH ≤ 4.6 or ≥ 8.
Part B: Absolute Change From Baseline In Haptoglobin at 1, 2, 4, 8, 12, and 24 Weeks Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24 Blood samples were planned to be collected to evaluate the effect of Isatuximab on marker of hemolysis: Haptoglobin. Baseline was defined as the last assessment value before IMP
Part B: Number Of Participants With Anti-Isatuximab Antibodies Up to Days 169 Plasma samples were planned to be collected to evaluate antibodies to Isatuximab. Plasma samples were planned to be screened for antibodies binding to Isatuximab. Post-baseline positive, defined as ADA that developed at any time during the ADA on-study observation period in participants without pre-existing ADA.
Part A: Area Under the Plasma Concentration Versus Time Curve Calculated Using the Trapezoidal Method From Time Zero to Time of the Last Concentration Observed Above the Lower Limit of Quantification (Clast) (AUClast) of Isatuximab Post-dose on Day 1 Blood samples were collected at the specified timepoints. AUClast was defined as area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to time of the Clast. The non-compartmental PK analysis was performed.
Part A: Number Of Participants With Anti-Isatuximab Antibodies Up to Days 169 Plasma samples were collected to evaluate antibodies to Isatuximab. Plasma samples were screened for antibodies binding to Isatuximab. Post-baseline positive, defined as Anti-drug antibody (ADA) that developed at any time during the ADA on-study observation period in participants without pre-existing ADA. Number of participants with positive ADA have been reported.
Part A: Mean Plasma Trough Concentration Of Isatuximab Post-dose on Days 15, 29, 43 and 57 Blood samples were collected at the specified timepoints. The non-compartmental Pharmacokinetic (PK) analysis was performed
Part B: Number of Participants With PCSA: Clinical Chemistry And Electrolyte Parameters From first dose of study drug (Day 1) up to end of study, approximately 169 days Blood samples were planned to be collected to determine the clinical chemistry laboratory and electrolyte parameters significant abnormalities. PCSA values were defined as abnormal values considered medically important by the Sponsor, according to predefined criteria/thresholds based on literature reviews and defined by the Sponsor. Criteria for PCSA: Glucose: ≤ 3.9 mmol/L and \< LLN, ≥ 11.1 mmol/L (unfasted); ≥ 7 mmol/L (fasted); Creatinine: ≥ 150 µmol/L, ≥ 30% change from baseline, ≥ 100% change from baseline, ALT: \> 3 ULN, \> 5 ULN, \> 10 ULN; AST: \> 3 ULN; ALP: \> 1.5 ULN; Total Bilirubin: \> 1.5 ULN, \> 2 ULN; Sodium: ≤ 129 mmol/L; ≥ 160 mmol/L; Potassium: \< 3 mmol/L, ≥ 5.5 mmol/L and Calcium
Part B: Overall Response Rate (Response [R] Or Complete Response [CR]) At Day 169 Day 169 Overall response rate was defined as the percentage of participants with a R or CR over the evaluable participants. R was defined as an increase in Hb by ≥2 g/dL from baseline and an absence of transfusion in the last 7 days and absence of rescue medications in the past 4 weeks. Biochemical evidence of hemolysis might still be present. CR was defined as Hb ≥11 g/dL (women) or ≥12 g/dL (men), no evidence of hemolysis (normal bilirubin, LDH, haptoglobin, and reticulocytes), and absence of transfusion in the last 7 days and absence of rescue medication in the past 4 weeks
Part B: Absolute Change From Baseline In LDH at 1, 2, 4, 8, 12, and 24 Weeks Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24 Blood samples were planned to be collected to evaluate the effect of Isatuximab on marker of hemolysis: LDH. Baseline was defined as the last assessment value before IMP
Part B: Number of Participants With TEAEs And TESAEs From first dose of study drug (Day 1) up to end of study, approximately 169 days An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAE is defined as an AE that occurred from the time of the first IMP administration up to 30 days (included) after the last IMP administration. A SAE is defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, was a medically important event.
Part B: Absolute Change From Baseline In Total Bilirubin at 1, 2, 4, 8, 12, and 24 Weeks Baseline (Day 1) and pre-dose at Weeks 1, 2, 4, 8, 12, and 24 Blood samples were planned to be collected to evaluate the effect of Isatuximab on marker of hemolysis: Total Bilirubin. Baseline was defined as the last assessment value before IMP
Trial Locations
- Locations (6)
Investigational Site Number : 3800001
🇮🇹Milano, Italy
Investigational Site Number : 2500001
🇫🇷Creteil Cedex, France
Investigational Site Number : 8260001
🇬🇧London, London, City Of, United Kingdom
Investigational Site Number : 2760001
🇩🇪Essen, Germany
Fox Chase Cancer Center Site Number : 8400004
🇺🇸Philadelphia, Pennsylvania, United States
Investigational Site Number : 5280001
🇳🇱Leiden, Netherlands