Immunoglobulin A nephropathy (IgAN) is a kidney condition. It happens when the body's immune system creates groups of proteins (called immune complexes) that build-up in the kidneys causing swelling (inflammation). Over time, this inflammation may lead to kidney damage and cause the kidneys to no longer work properly. The main aim of this study is to check how well mezagitamab changes protein levels in the urine (proteinuria) compared to placebo in adults with primary IgAN. A placebo looks like medicine but doesn't have any active ingredients in it. Other aims are to check how safe mezagitamab is and how well participants with primary IgAN can tolerate it compared to placebo, and to find out if and how well mezagitamab continues to maintain kidney function over the long term compared to placebo.

Participants will be placed in 1 of the 2 treatment groups; the main group and the open-label group. In the main group, participants will be placed in 1 of the 2 treatment groups by chance (either mezagitamab or placebo) at a 2:1 ratio. This means that out of 3 participants, 2 will receive mezagitamab and 1 will receive placebo. The participants will receive either mezagitamab or placebo for almost half a year in two 1-year cycles. They will be observed for another half year in each 1-year cycle and will have check-ups about every month during this time.

In the open-label group, a small number of participants who have lower levels of protein in their urine or have kidneys that do not filter the blood well, will receive mezagitamab treatment. This will include participants who have previously received mezagitamab in another study, TAK-079-1006. Every participant will receive mezagitamab in the same way as those in the main group receiving mezagitamab.

During the study, participants will visit their study clinic several times.

• Inclusion Criteria:

To be eligible to participate in this trial, participants must meet all the following criteria:

1. Either UPCR greater than or equal to (≥) 0.8 gram per gram (g/g) or urine protein excretion (UPE) ≥1 grams per day (g/day), calculated from at least one 24-hour urine collection during the screening period (or pre-screening, if applicable) (only applicable for the main trial).

2. eGFR greater than (>)30 milliliters per minute per 1.73 meter square (mL/min/1.73m^2) at screening based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (only applicable for the main trial).

3. No prior exposure to anti- cluster of differentiation 38 (CD38) therapy period (except for open-label cohort participants meeting Inclusion Criterion No. 10.a).

4. The participant is aged ≥ 18 years or the local legal age as applicable.

5. The participant (and the participant's legally acceptable representative, as applicable per local regulations or determination) has provided informed consent (that is, in writing, documented via a signed and dated informed consent form [ICF]) and any required privacy authorization before the initiation of any clinical trial procedures.

6. Diagnosis of primary immunoglobulin A nephropathy (IgAN) supported by a renal biopsy report that is dated more recently than 10 years before the signing of the informed consent for the clinical trial. The redacted report must be made available for review. A renal biopsy must be performed during screening for participants without a biopsy report within 10 years.

7. Participants must be on stable renin-angiotensin-aldosterone system (RAAS) inhibitor therapy with an angiotensin-converting enzyme inhibitor (ACE-I) and/or angiotensin receptor blocker (ARB) or endothelin receptor antagonist (ERA) or mineralocorticoid receptor antagonist (MRA) agent for at least 12 weeks before signing the ICF with dosing at the maximally tolerated or labeled dose as determined by the investigator, with the intent to continue stable dosing during the clinical trial. Those intolerant of RAAS inhibitor therapy are potentially eligible after consultation with the medical monitor. Intolerance is defined as a documented side effect causing discontinuation of the therapy.

8. Resting blood pressure less than or equal to (≤)150 millimeters of mercury (mmHg) systolic and ≤100 mmHg diastolic.

9. Female participants of childbearing potential who are not pregnant during screening (confirmed by negative serum human chorionic gonadotropin [hCG]) and on Visit 1 before first dose of trial intervention (confirmed by negative urine pregnancy test).

10. Any one of the following (only applicable for participants in the open-label cohort):

    1. Participants in Trial TAK-079-1006 who completed the Week 96 visit or the retreatment period with either UPCR >0.5 g/g or UPE >0.5 g/d calculated from a 24-hour urine collection during the screening period (or pre-screening, if applicable) and eGFR >30 mL/min/1.73m^2 at screening based on the CKD-EPI formula.

    2. UPCR <0.8 g/g and UPE ≥0.75 and <1.0 g/day, by 24-hour urine collection during the screening period (or pre-screening, if applicable) and eGFR > 30 mL/min/1.73m^2 at screening based on the CKD-EPI formula.

    3. UPCR ≥ 0.8 g/g or UPE ≥ 1.0 g/d by 24-hour urine collection during the screening period (or pre-screening, if applicable) and eGFR ≥25 and ≤30 mL/min/1.73m^2 at screening based on the CKD-EPI formula.

       • Exclusion Criteria:

A participant who meets any of the following criteria will be excluded from participation in this trial:

1. Kidney biopsy exhibiting significant concomitant renal disease other than IgAN (for example, diabetic nephropathy, lupus nephritis, minimal change disease).

2. Secondary IgAN (such as with significant liver disease, inflammatory bowel disease, and seronegative spondyloarthropathies), and immunoglobulin A (IgA) vasculitis.

3. Evidence of rapidly progressive glomerulonephritis (loss of ≥50% of eGFR within 3 months before the signing of the ICF).

4. Diagnosis of nephrotic syndrome defined as 24-hour proteinuria >3.5 g/day and hypoalbuminemia (<3.0 grams per deciliter [g/dL]) with or without peripheral edema.

5. Renal or other organ transplantation prior to or expected during the clinical trial.

6. Treatment with oral immunosuppressive agents (including cyclophosphamide, mycophenolate mofetil, cyclosporine, azathioprine, calcineurin inhibitors) or biologic therapy for immunomodulation (including immunomodulatory monoclonal or polyclonal antibodies) within 6 months (both B-cell and non-B-cell directed agents) before signing of the ICF.

7. If the participant has received anti-CD20 treatment, the participant is excluded if either of the following apply:

   1. The last dose was received within 6 months before the signing of the ICF.
   2. The last dose was received between 6 and 12 months before the signing of the ICF and the participant has a CD19+ count below the lower limit of normal.

   Note: Participants who have received the last dose of anti-CD20 treatment >12 months before the signing of the ICF are not excluded from clinical trial participation based on this criterion and are not required to undergo CD19+ testing.

8. Within 4 months of the screening visit, use of either a) systemic corticosteroids at an average dose of 40 milligrams (mg) prednisone equivalent or higher for more than 14 days or b) oral budesonide delayed release capsules.

9. The participant has received a live or live-attenuated vaccine within 4 weeks before signing the ICF or has any live or live-attenuated vaccine planned during the clinical trial.

10. Participation in any other investigational drug trial (including vaccine trial) with receipt of at least 1 dose of investigational drug, or has been exposed to another investigational agent within 4 weeks or 5 half-lives, whichever is longer, before Visit 1.

11. The participant has active infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).

12. The participant has had any of the following types of infections within the specified timeframes where applicable:

    1. Active bacterial, viral, or fungal infection (except for the common cold and onychomycosis), or any other serious infection within 2 weeks of signing the ICF. Any anti-infective course for infection must be completed at least 2 weeks before Visit 1.
    2. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) infection within 4 weeks of signing the ICF.
    3. Opportunistic infection or treatment for an opportunistic infection less than or equal to (≤)12 weeks before signing the ICF.
    4. Active tuberculosis (TB), any history of prior active TB, or any signs or symptoms of active TB infection (including but not limited to chronic fever, chronic productive cough, night sweats, weight loss, or malnutrition) as judged by the investigator.
    5. For participants in European Union (EU) member states, positive or 2 indeterminant QuantiFERON results, unless there is documentation of prior complete treatment for latent TB, or participant has initiated prophylaxis based on local guidelines and in consultation with a pulmonology or infectious disease specialist prior to the first administration of IMP.

13. In the opinion of the investigator, the participant is currently experiencing any medical condition that might interfere with participation in the trial (for example, significant ocular, cardiovascular, pulmonary, hematologic, gastrointestinal, endocrinologic, hepatic, renal, neurologic, malignancy, infectious disease, immunodeficiency, or alcohol and drug abuse), that poses an added risk for the participant or could confound the assessment of trial results.

14. In the opinion of the investigator, the participant has a serious medical or psychiatric illness that could potentially interfere with the completion of treatment.

15. The participant has a history of major surgery within 3 months before screening (or longer, at the discretion of the investigator); or, either has a planned tonsillectomy or underwent a tonsillectomy within 6 months before screening.

    Note: Major surgery typically requires at least 1 night in the hospital.

16. History of malignancy (including myelodysplastic syndrome) within 5 years of signing the ICF, except for adequately treated non-melanoma skin cancer, superficial bladder cancer, and curatively treated cervical carcinoma-in-situ.

17. The participant has a history of a severe allergic or anaphylactic reaction to recombinant proteins or excipients used in the mezagitamab or placebo formulation.

18. The participant has (1) been diagnosed with or has suspected chronic obstructive pulmonary disease (COPD) or asthma and (2) has a prebronchodilatory forced expiratory volume in 1 second (FEV1) <50% of predicted normal at screening.

19. The participant is capable of breastfeeding but does not agree to forego breastfeeding from first dose of investigational medicinal product (IMP) through 30 days after the last dose of IMP.

20. The participant is an individual with potential for pregnancy but does not agree to use at least 1 form of highly effective contraception and 1 barrier method of contraception (preferably male condom) when engaging in heterosexual sex for the protocol specified duration after the last dose of IMP.

21. The participant is a sexually active, non-sterilized individual who produces sperm but does not agree to use a barrier method (preferably male condom) combined with at least 1 form of highly effective contraception for any partner(s) with potential for pregnancy when engaging in heterosexual sex for the protocol specified duration after the last dose of IMP.

22. In the investigator's opinion, the participant (and the participant's legally acceptable representative, if applicable per local regulations or determination) is unwilling and/or unable to understand and fully comply with clinical trial procedures and requirements (including digital tools and applications).

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.