Business decision

The main purpose of this study is to evaluate the efficacy of RYMPHYSIA [Alpha1-Proteinase Inhibitor (Human)] compared to another available alpha-1 proteinase Inhibitor (A1PI) in adults with A1PI deficiency and COPD-emphysema.

In Part A of the study, participants will be randomly assigned to receive either RYMPHYSIA or another available A1PI for 104 weeks. Participants who were randomized to another available A1PI will enter a 2-week follow-up period after the treatment phase is completed; participants who were randomized to RYMPHYSIA will enter Part B.

In Part B, participants will be randomly assigned to one of two groups and will receive either the same dose of RYMPHYSIA as in Part A or a different dose for an additional 104 weeks, followed by a 2-week follow-up period.

Inclusion:

• Adult 18 to 75 years at the time of screening.

• Diagnosis of alpha1-proteinase inhibitor (A1PI) deficiency, defined as follows:

  • Endogenous serum A1PI level lesser than (<)11 micromolar (μM) or 57.2 micrograms per deciliter (mg/dL) (0.572 gram per liter [g/L]) (as measured at the end of the washout, if applicable)
  • Genotype ZZ, Z/null, null/null, MMalton/Z, or others that result in A1PI levels <11 μM. Prior documentation of genotype will be sufficient, or genotyping will be offered at the time of screening

• Participants eligible for enrollment include newly diagnosed, previously untreated, currently treated, and currently not on treatment but who have received treatment in the past. For those currently on augmentation therapy, a 2-week minimum washout is required until A1PI levels are <11 μM.

• Clinically evident chronic obstructive pulmonary disease (COPD)-emphysema at the time of screening defined by post-bronchodilator FEV1 of greater than or equal to (≥)30 percent (%) and lesser than or equal to (≤)80% predicted and FEV1/forced vital capacity (FVC) <70%, corresponding to mild to severe COPD (according to Global Initiative for Chronic Obstructive Lung Disease [GOLD] Criteria, stage I-III) (Global Initiative for Chronic Obstructive Lung Disease 2021) and evidence of emphysema on chest imaging (confirmed by the baseline computer topography [CT] densitometry scan).

• If treated with any respiratory medications including inhaled bronchodilators, inhaled corticosteroids, or systemic corticosteroids (e.g., prednisone ≤10 micrograms per day [mg/day] or its equivalent), the doses of medications should have remained stable for at least 28 days prior to screening.

• No clinically significant abnormalities (other than emphysema, bronchitis, or bronchiectasis) detected via chest imaging at the time of screening.

• Males and non-pregnant, non-lactating females whose screening pregnancy test is negative and willing and able to employ adequate contraceptive methods.

• Willing and able to refrain from smoking (including e-cigarettes and vaping of any other substance) for the duration of study.

• Willing and able to comply with the requirements of the protocol and able to voluntarily provide written, signed, and dated (personally or via a legally authorized representative) informed consent to participate in the study.

Exclusion:

• Known ongoing or history of clinically significant disease other than respiratory or liver disease secondary to A1PI deficiency.
• If experiencing COVID-19, lower respiratory tract infection (LRTI) and/or acute COPD exacerbation at the time of screening. Participants may be re-screened after clinical resolution of COVID-19, LRTI and/or acute COPD exacerbation and must have also remained stable for at least 6 weeks after the onset of illness.
• Known ongoing or history of clinically significant cor pulmonale and/or congestive heart failure with New York Heart Association (NYHA) Class III/IV symptoms.
• Has received an organ transplant, has undergone major lung surgery (e.g., lung volume reduction surgery or lobectomy surgery), or is currently on a transplant waiting list.
• Experiencing an active malignancy or has a history of malignancy within 5 years prior to screening, with the exception of the following: adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or stable prostate cancer not requiring treatment.
• Current active smoker (including e-cigarettes or vaping, nicotine or any other substance). A participant with a previous history of smoking has to have ceased active smoking at least 6 months prior to screening. Participants with a positive nicotine/cotinine test due to nicotine replacement therapy (eg, patches, chewing gum) or snuff are eligible.
• Receiving long-term therapy (>28 days) of parenteral corticosteroids or oral corticosteroids at doses greater than 10 mg/day of prednisone or its equivalent.
• Receiving chronic 24 hours/day oxygen supplementation (other than for an acute COPD exacerbation, or supplemental oxygen with continuous positive airway pressure [CPAP], or bi-level positive airway pressure [BiPAP] for acute respiratory failure).
• Known selective immunoglobulin A (IgA) deficiency (IgA level <7 mg/dL at screening) with anti-IgA antibodies and a history of any hypersensitivity reaction.
• Known history of hypersensitivity following infusions of human immunoglobulins, human albumin, blood or blood components.
• Presence of clinically significant laboratory abnormalities at the screening that in the opinion of the investigator would impact the participant's safety if enrolled in the study.
• Presence of any of the following that, in the opinion of the investigator, would affect participant's safety or compliance or confound the results of the study, including known clinically significant medical, psychiatric, or cognitive illness, is a recreational drug/alcohol user, or has any other uncontrolled medical condition (e.g., unstable angina, transient ischemic attack, uncontrolled hypertension).
• Known exposure to another investigational product/investigational medicinal product (IP/IMP) within 28 days prior to enrollment or is scheduled to participate in another clinical study involving an IP/IMP or investigational device during this study.
• Participant is a family member or employee of the investigator.
• If female, participant is pregnant or nursing at the time of enrollment.

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/ For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.