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Safety, Tolerability, PK and PD of ADX-038 in HV and Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients

PHASE1RECRUITING

The first-in-human Phase 1 study described herein will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ADX-038 in both healthy volunteers (HV) and in patients with paroxysmal nocturnal hemoglobinuria (PNH).

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Study details:

The clinical study described in this protocol is a Phase 1, single-center study evaluating safety, tolerability, PK, and PD of ADX-038. The study consists of 2 parts:. 1.

Part A - Randomized, double-blind, placebo-controlled, parallel group, single ascending dose (SAD) in HV with up to 5 dose cohorts. 2. Part B - Expansion cohort in participants with paroxysmal nocturnal hemoglobinuria (PNH) at selected dose from Part A and will be open label.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Male and female adults 18 to 65 years old

Serum LDH levels are at least 1.25-fold above the ULN at screening

Mean hemoglobin (Hb) <12 g/dL

A history of red blood cell (RBC) transfusion due to PNH within at least 3 months of screening

Body mass index (BMI) between 18 and 30 kg/m2

Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

Willing and able to provide informed consent and comply with all study visits and procedures

Neisseria meningitis vaccination

Pneumococcus vaccination

Hemophilus influenzae vaccination

Confirmed diagnosis of PNH based on documented clone size of PNH blood cells by flow cytometry

Liver function test values are less than 2x ULN

Exclusion criteria

Known or suspected hereditary or acquired complement deficiency

History of clinically significant arterial or venous thrombosis, or current history of a clinically significant prothrombotic risk

History of hematopoietic stem cell transplantation

History of meningococcal infection

Any significant medical history

Active malignancy and/or history of malignancy in the past 5 years

Any active viral, bacterial, parasitic, or fungal infection or acute illness, inclusive of cold/flu, herpes zoster, or COVID-19, within 30 days prior to the first study drug administration

Any evidence of sero-positive autoimmune connective tissue diseases

Any evidence of active inflammatory conditions (including inflammatory bowel disease or cryoglobulinemia)

History of previous or current tuberculosis infection

Prior splenectomy

Major surgery or significant traumatic injury occurring within 3 months prior to signature of the PICF.

Have any other conditions that, in the opinion of the Investigator or Sponsor, would make the participant unsuitable for inclusion

Liver impairment, history of liver disease, Gilbert's syndrome, or abnormal liver function tests at screening and/or admission.

Positive serology tests for human immunodeficiency virus hepatitis B surface antigen or hepatitis C virus

Use of any prescription, vaccines, supplements/vitamins, or over-the counter medication

Treatment with another investigational product within 30 days

Known any clinically significant allergic reactions

Known hypersensitivity to any of the study drug ingredients or penicillin.

History or presence of alcohol

Blood donation

Pregnancy

May have a higher risk to be exposed to infected individuals, for example active healthcare employees.

Inadequate organ function

Supine systolic blood pressure <90 or >160 mmHg, supine diastolic blood pressure <50 or >95 mmHg, pulse rate <45 or >100 beats per minute (bpm), or elevated body temperature (>37.5 ºC) prior to dosing.

Willing to continue after enrollment with their current treatment with a complement inhibitor.

Use of vaccines, or changes in any prescription, supplements/vitamins, or over-the counter medication

Treatment with another investigational product or biologic agent within 30 days

History or presence of alcohol abuse

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : Yes

Gender eligible for study: All

Things to know

Study dates

Study start: 2023-07-03

Primary completion: 2024-11-30

Study completion finish: 2025-06-30

Study type

TREATMENT

Phase

PHASE1

Trial ID

NCT05876312

Intervention or treatment

DRUG: ADX-038

DRUG: Placebo

Conditions

• Paroxysmal Nocturnal Hemoglobinuria (PNH)

Image related to Paroxysmal Nocturnal Hemoglobinuria (PNH)

Condition: Paroxysmal Nocturnal Hemoglobinuria (PNH)
DRUG: ADX-038 and other drugs
Melbourne, Victoria, Australia and more
Sponsor: ADARx Pharmaceuticals, Inc.

You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.

Are you running this trial? If you're a clinic or sponsor, you can claim this study. Claim or learn more.

Find a site

Closest Location:

Peter MacCallum Cancer Centre

Research sites nearby

Select from list below to view details:

Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia
Royal Melbourne Hospital
Parkville, Victoria, Australia
Nucleus Network Brisbane
Brisbane, Queensland, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: PART A - Active ADX-038 administered to HV For each cohort in Part A (SAD), 8 participants will be randomized in a 3:1 ratio; 6 participants to active (ADX-038): 2 participants to control (matched placebo). Randomization will be on Day 1. Initially, 2 sentinel participants (1 active and 1 placebo) will be randomized and dosed. The sentinel participants will be evaluated for safety. The investigator's assessment and the independent medical monitor will decide upon the randomization and dosing of the 6 remaining participants (5 active and 1 placebo) according to the randomization schedule.	DRUG: ADX-038 siRNA duplex oligonucleotide
PLACEBO_COMPARATOR: PART A- Placebo administered to HV For each cohort in Part A (SAD), 8 participants will be randomized in a 3:1 ratio; 6 participants to active (ADX-038): 2 participants to control (matched placebo). Randomization will be on Day 1. Initially, 2 sentinel participants (1 active and 1 placebo) will be randomized and dosed. The sentinel participants will be evaluated for safety. The investigator's assessment and the independent medical monitor will decide upon the randomization and dosing of the 6 remaining participants (5 active and 1 placebo) according to the randomization schedule.	DRUG: Placebo Saline
EXPERIMENTAL: PART B - ADX-038 administered to PNH participants This will be initiated at the dose level determined by the Safety Review Committee from SAD in HVs. The treatment of HAE participants is an open-label study.	DRUG: ADX-038 siRNA duplex oligonucleotide

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Safety in Healthy Volunteers	To evaluate the safety and tolerability of ADX-038 in HVs by incidence, relationship, and severity of adverse events and serious adverse events	365 days
Safety in Healthy Volunteers	To evaluate the safety and tolerability of ADX-038 in HVs by change in baseline electrocardiogram (ECG) parameters (PR, QRS, QT, and QTcF intervals)	365 days
Safety in Paroxysmal Nocturnal Hemoglobinuria	To evaluate the safety and tolerability of ADX-038 in HVs by change in baseline electrocardiogram (ECG) parameters (PR, QRS, QT, and QTcF intervals)	365 days
Safety in Paroxysmal Nocturnal Hemoglobinuria	To evaluate the safety and tolerability of ADX-038 in HAE by incidence, relationship, and severity of adverse events and serious adverse events	365 days

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Maximum observed concentration (Cmax)	8 days
Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria	To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Maximum observed concentration (Cmax)	8 days
Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Time to Cmax (Tmax)	8 days
Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria	To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Time to Cmax (Tmax)	8 days
Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Area under the concentration-time curve from 0 to time of last quantifiable concentration (AUC0-last)	8 days
Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria	To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Area under the concentration-time curve from 0 to time of last quantifiable concentration (AUC0-last)	8 days
Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Area under the concentration-time curve from 0 to infinity (AUC0-∞)	8 days
Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria	To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Area under the concentration-time curve from 0 to infinity (AUC0-∞)	8 days
Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Apparent terminal half-life (t½)	8 days
Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria	To characterize the Pharmacokinetics of ADX-038 in HVs by measuring the Apparent terminal half-life (t½)	8 days
Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Terminal elimination rate constant (λz)	8 days
Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria	To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Terminal elimination rate constant (λz)	8 days
Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Total apparent body clearance (CL/F)	8 days
Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria	To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Total apparent body clearance (CL/F)	8 days
Pharmacokinetics in Healthy Volunteers	To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Apparent volume of distribution (Vz/F)	8 days
Pharmacokinetics in Paroxysmal Nocturnal Hemoglobinuria	To characterize the Pharmacokinetics of ADX-038 in HVs measuring the Apparent volume of distribution (Vz/F)	8 days
Pharmacodynamics in Healthy Volunteers	Change from base in plasma concentrations over time in Complement factor B (CFB) protein	365 days
Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria	Change from base in plasma concentrations over time in Complement factor B (CFB) protein	365 days
Pharmacodynamics in Healthy Volunteers	Change from base in plasma concentrations over time in change in complement alternative pathway activity via assay measurement	365 days
Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria	Change from base in plasma concentrations over time in change in complement alternative pathway activity via assay measurement	365 days
Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria	Change from baseline in lactate dehydrogenase	365 days
Pharmacodynamics in Paroxysmal Nocturnal Hemoglobinuria	Change from baseline in total hemoglobin	365 days

Frequently Asked Questions

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References

Clinical Trials Gov: Safety, Tolerability, PK and PD of ADX-038 in HV and Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients