A Study to Evaluate the Efficacy and Safety of Pegcetacoplan in Patients With Cold Agglutinin Disease (CAD)

Swedish Orphan Biovitrum24 enrolled

Overview

The purpose of the study is to determine the efficacy of pegcetacoplan administration compared to placebo in increasing hemoglobin (Hgb) level from baseline and avoiding transfusion in participants with primary cold agglutinin disease (CAD).

This is a blind (actual treatment not disclosed to Investigator or participant) study to study pegcetacoplan in people with cold agglutinin disease. The study will consist of a 4-week screening period where selected tests will be conducted to ensure that the patient is eligible to participate in the study, followed by Part A, a 24-week blinded treatment period where the participants will receive either pegcetacoplan or a placebo treatment, looking like pegcetacoplan but with no effect. After this period, the participants will move into Part B, a 24-week period where they will all receive pegcetacoplan. Part C is a 48-week maintenance period with pegcetacoplan for all participants. After the end of treatment participants will undergo a safety follow visit about 8 weeks after last dose. All eligible study participants will receive pegcetacoplan or placebo treatment, administered via subcutaneous infusion twice a week at home. The subcutaneous infusion requires two small needles to be inserted into the fatty layer of tissue under the skin and the investigational medication will flow into the body. Study participants and/or caregivers will be trained on home administration of pegcetacoplan.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Cold Agglutinin Disease

Interventions

PegcetacoplanDRUG

Pegcetacoplan taken twice weekly as subcutaneous injection

Placebo matching PegcetacoplanDRUG

Placebo matching pegcetacoplan taken twice weekly as subcutaneous injection

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age 18 years or older. 2. Diagnosis of primary CAD. 3. Hb level ≤ 9 g/dL. 4. Documented results from bone marrow biopsy within 1 year of screening 5. Either have vaccination against Streptococcus pneumoniae, Neisseria meningitidis (Types A, C, W, Y, and B), and Haemophilus influenzae (Type B) within 2 years prior to screening or agree to receive vaccination during screening. 6. Women of childbearing potential (WOCBP), defined as any women who have experienced menarche and who are NOT permanently sterile or postmenopausal, must have a negative pregnancy test at screening and agree to use protocol-defined methods of contraception for the duration of the study and 8 weeks after their last investigational medicinal product (IMP) dose. 7. Men must agree to the following for the duration of the study and 8 weeks after their last IMP dose: 1. Avoid fathering a child. 2. Use protocol-defined methods of contraception. 3. Refrain from donating sperm. 8. Willing and able to give written informed consent. Exclusion Criteria: 1. Have received other anti-complement therapies (approved or investigational) within 5 half-lives of the agent prior to randomization. 2. Treatment with rituximab monotherapy within 12 weeks prior to randomization, or rituximab combination therapies (e.g., with bendamustine, fludarabine, other cytotoxic drugs or ibrutinib) within 16 weeks prior to randomization. 3. Diagnosis of systemic lupus erythematosus or other autoimmune diseases with antinuclear antibodies. 4. History of an aggressive lymphoma or presence of a lymphoma requiring therapy. 5. Have received an organ transplant. 6. Cold agglutinin syndrome secondary to Mycoplasma pneumoniae, Epstein-Barr virus or other specific causative infection. 7. Presence or suspicion of liver dysfunction as indicated by elevated alanine aminotransferase (ALT) \> 2.5 x upper limit of normal (ULN), or direct bilirubin levels \> 2 x ULN. 8. Inability to cooperate with study procedures.

Locations (44)

Outcomes

Primary Outcomes

Number of Patients Achieving a Response (R) at Week 24

A participant was considered to have a response if the Hgb level increased greater than or equal to (\>=) 1.5 gram per deciliter (g/dL) from baseline and this increase was maintained from Week 16 through Week 24 in absence of blood transfusion from Week 5 through Week 24.

Time frame: Week 24

Secondary Outcomes

Change From Baseline to Week 24 in Hemoglobin (Hgb) Level-Part A in the Absence of Intercurrent Events (ICEs).

Time frame: Week 24

Number of Patients Achieving Transfusion Avoidance From Week 5 to Week 24-Part A

Percentage of patients who did not receive a blood transfusion between Week 5 and Week 24 was assessed

Time frame: Week 24

Change From Baseline to Week 24 in FACT-An Scale Score (Quality of Life)-Part A in the Absence of Intercurrent Events (ICEs)

The ICEs of interest were : * Withdrawal from treatment or lost to follow-up before the end of the double-blind period * Use of prohibited medications (rituximab alone or in combination, any other complement inhibitor, any other investigational drug, and plasma exchange). FACT-An is used to measure quality of life (QoL) in patients with anemia. Each item is rated on a 5-point Likert scale:0=Not at all, 1=A little bit ,2=Somewhat, 3=Quite a bit, 4=Very much. Some items are reverse scored. Higher scores in this scale denote a better QoL with less impact of anemia.The total FACT-An scale score ranges from 0 to 160. The total score gives a comprehensive view of a patient's well-being. It combines the FACT-G with an Anemia subscale. FACT-G (27 items):Physical Well-Being (PWB) and Social/Family Well-Being (SWB) 14 items in total, Emotional Well-Being (EWB)-6 items,Functional Well-Being (FWB)-7 items, Anemia Subscale (AnS): 13 items. Total FACT-An score=FACT-G + Anemia Subscale=40 item

Data from ClinicalTrials.gov

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Number of Packed Red Blood Cell Transfusions Received by Patients From Week 5 to Week 24-Part A

Number of blood transfusions received between Week 5 and Week 24 were assessed.

Time frame: Week 24

Change From Baseline to Week 24 in LDH Levels-Part A in the Absence of Intercurrent Events (ICEs)

Time frame: Week 24

Change From Baseline to Week 24 in Haptoglobin Levels-Part A in the Absence of Intercurrent Events (ICEs)

Time frame: Week 24

Change From Baseline to Week 24 in Indirect Bilirubin-Part A in the Absence of Intercurrent Events (ICE)

Time frame: Week 24

Change From Baseline to Week 24 in ARC-Part A in the Absence of Intercurrent Events (ICEs)

Time frame: Week 24

Change From Baseline to Week 24 in D-dimer Levels-Part A in the Absence of Intercurrent Events (ICEs

* Withdrawal from treatment or lost to follow-up before the end of the double-blind period * Use of prohibited medications (rituximab alone or in combination, any other complement inhibitor, any other investigational drug, and plasma exchange) change from baseline to Week 24 in D-dimer levels.

Time frame: Week 24

Normalization of Markers of Hemolysis (LDH) at Week 24-Part A

Percentage of patients with LDH level within normal ranges and with an abnormal value at baseline.

Time frame: Week 24

Normalization of Markers of Hemolysis (Indirect Bilirubin) at Week 24-Part A

Percentage of patients with Indirect Bilirubin level within normal ranges and with an abnormal value at baseline.

Time frame: Week 24

Normalization of Markers of Hemolysis (ARC) at Week 24-Part A

Percentage of patients with ARC level within normal ranges and with an abnormal value at baseline.

Time frame: Week 24

Normalization of Markers of Hemolysis (Haptoglobin) at Week 24-Part A

Percentage of patients with haptoglobin level within normal ranges and with an abnormal value at baseline.

Time frame: Week 24

Count and Percentage of Patients With a First Normalization From Baseline by Week 24 for Haptoglobin Levels-Part A

Percentage of patients with haptoglobin level normalization during the initial 24 weeks of the study

Time frame: Week 24

Count and Percentage of Patients With a First Normalization From Baseline by Week 24 for Hemoglobin Levels-Part A

Percentage of patients with Hemoglobin level normalization during the initial 24 weeks of the study

Time frame: Week 24

Count and Percentage of Patients With a First Normalization From Baseline by Week 24 for LDH Levels-Part A

Percentage of patients with LDH level normalization during the initial 24 weeks of the study

Time frame: Week 24

Count and Percentage of Patients With a First Normalization From Baseline by Week 24 for Indirect Bilirubin Levels-Part A

Percentage of patients with Indirect Bilirubin level normalization during the initial 24 weeks of the study

Time frame: Week 24

Count and Percentage of Patients With a First Normalization From Baseline by Week 24 for ARC Levels-Part A

Percentage of patients with ARC level normalization during the initial 24 weeks of the study

Time frame: Week 24

Number of Packed Red Blood Cell Units Transfused From Week 5 to Week 24-Part A

Number of PRBC units transfused from Week 5 and Week 24 was assessed

Time frame: Week 5 to Week 24

Change From Baseline to Week 24 in FACIT-F Subscale Score-Part A in the Absence of Intercurrent Events (ICEs)

The ICEs of interest were : * Withdrawal from treatment or lost to follow-up before the end of the double-blind period * Use of prohibited medications (rituximab alone or in combination, any other complement inhibitor, any other investigational drug, and plasma exchange). The FACIT-F subscale is used to measure fatigue and its impact upon daily activities and function in patients with chronic illnesses and contains 20 items related to the impact of fatigue. Each item is scored on a 0-4 scale, with some items reverse-scored. Total scores range from 0 to 52, where higher scores indicate less fatigue and better outcomes, and lower scores reflect greater fatigue. It can be used alone or with other FACIT subscales as part of broader quality of life assessments.

Time frame: Week 24

Change From Baseline to Week 24 in SF-12-Part A in the Absence of Intercurrent Events (ICEs)

The ICEs of interest were : * Withdrawal from treatment or lost to follow-up before the end of the double-blind period * Use of prohibited medications (rituximab alone or in combination, any other complement inhibitor, any other investigational drug, and plasma exchange. SF-12 is a 12-item health survey assessing physical and mental health. Higher scores mean better health with scores above 50 indicating better than average health. It produces two summary scores: the Physical Component Summary (PCS) and Mental Component Summary (MCS), both norm-based (mean=50, SD=10), with ranges of \~5-80 (PCS) and \~-3.3-80 (MCS). Higher scores=better health. It also covers 8 subscales-Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role-Emotional (RE), and Mental Health (MH), each scored between 0-100, where higher=better functioning. Scores are computed using weighted formulas from item responses (not simple averages).

Time frame: Week 24

Change From Baseline to Week 24 in EQ-5D-5L Questionnaire -Part A in the Absence of Intercurrent Events (ICEs)

The EQ-5D-5L measures total health across 5 dimensions: Mobility, Self-care, Usual Activities, Pain/Discomfort, and Anxiety/Depression-each scored from 1 (no problems) to 5 (extreme problems). Scores form a 5-digit health profile (e.g., 12345). Each individual score plus a VAS for perceived health status today are separately reported. Higher scores reflect better total health. The EQ VAS is a patient-rated score from 0 (worst) to 100 (best health). The ICEs of interest were : * Withdrawal from treatment or lost to follow-up before the end of the of the double-blind period * Use of prohibited medications (rituximab alone or in combination, any other complement inhibitor, any other investigational drug, and plasma exchange).

Time frame: Week 24

Change From Baseline to Week 48 in Hemoglobin (Hgb) Level-Part B in the Absence of Intercurrent Events (ICEs).

Time frame: Week 48

Change From Baseline to Week 48 in LDH Level-Part B in the Absence of Intercurrent Events (ICEs).

Time frame: Week 48

Change From Baseline to Week 48 in Haptoglobin Level-Part B in the Absence of Intercurrent Events (ICEs).

Time frame: Week 48

Change From Baseline to Week 48 in Indirect Bilirubin Level-Part B in the Absence of Intercurrent Events (ICEs).

Time frame: Week 48

Change From Baseline to Week 48 in ARC-Part B in the Absence of Intercurrent Events (ICEs)

Time frame: Week 48

Change From Baseline to Week 48 in D-dimer Levels-Part B in the Absence of Intercurrent Events (ICEs).

Time frame: Week 48

Change From Baseline to Week 48 in FACT-An Scale Score (Quality of Life)-Part B in the Absence of Intercurrent Events (ICEs)

The ICEs of interest were : * Withdrawal from treatment or lost to follow-up before the end of the double-blind period * Use of prohibited medications (rituximab alone or in combination, any other complement inhibitor, any other investigational drug and plasma exchange. The FACT-An is used to measure quality of life (QoL) in patients with anemia. Each item is rated on a 5-point Likert scale:0=Not at all, 1=A little bit ,2=Somewhat, 3=Quite a bit, 4=Very much.Some items are reverse scored. Higher scores in this scale denote a better QoL with less impact of anemia. The total FACT-An scale score ranges from 0 to 160. The total score gives a comprehensive view of a patient's well-being. It combines the FACT-G with an Anemia subscale.FACT-G (27 items):Physical Well-Being (PWB) and Social/Family Well-Being (SWB) 14 items in total, Emotional Well-Being (EWB)-6 items, Functional Well-Being (FWB)-7 items, Anemia Subscale (AnS): 13 items. Total FACT-An score=FACT-G + Anemia Subscale=40 items

Time frame: Week 48

Change From Baseline to Week 48 in FACIT-F Subscale Score-Part B in the Absence of Intercurrent Events (ICEs).

The ICEs of interest were : * Withdrawal from treatment or lost to follow-up before the end of the double-blind period * Use of prohibited medications (rituximab alone or in combination, any other complement inhibitor, any other investigational drug, and plasma exchange). The FACIT-F subscale is used to measure fatigue and its impact upon daily activities and function in patients with chronic illnesses and contains 20 items related to the impact of fatigue. Each item is scored on a 0-4 scale, with some items reverse-scored. Total scores range from 0 to 52, where higher scores indicate less fatigue and better outcomes, and lower scores reflect greater fatigue. It can be used alone or with other FACIT subscales as part of broader quality of life assessments.

Time frame: Week 48

Change From Baseline to Week 48 in EQ-5D-5L-Part B in the Absence of Intercurrent Events (ICEs).

Time frame: Week 48

Change From Baseline to Week 48 in SF-12-Part B in the Absence of Intercurrent Events (ICEs).

The ICEs of interest were : * Withdrawal from treatment or lost to follow-up before the end of the double-blind period * Use of prohibited medications (rituximab alone or in combination, any other complement inhibitor, any other investigational drug, and plasma exchange SF-12 is a 12-item health survey assessing physical and mental health. Higher scores mean better health with scores above 50 indicating better than average health. It produces two summary scores: the Physical Component Summary (PCS) and Mental Component Summary (MCS), both norm-based (mean = 50, SD =10), with ranges of \~5-80 (PCS) and \~-3.3-80 (MCS). Higher scores = better health. It also covers 8 subscales-Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role-Emotional (RE), and Mental Health (MH), each scored between 0-100, where higher=better functioning. Scores are computed using weighted formulas from item responses (not simple averages).

Time frame: Week 48