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Sickle Cell AnemiaPhase 3NOHARM-MTDNCT03128515

Optimizing Hydroxyurea Therapy in Children With SCA In Malaria Endemic Areas

A Phase 3 study testing Hydroxyurea in people with Sickle Cell Anemia and Sickle Cell Disease, run by Indiana University at 1 site in Uganda.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM) study is the first placebo-controlled randomized clinical trial of hydroxyurea treatment in a malaria endemic region. Read more about this study

Who is it for?
Ages 24 to 72 months
Conditions the study is for
Sickle Cell Anemia, Sickle Cell Disease, Malaria
What is being tested?
Hydroxyurea
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
187 participants
Where
1 siteUganda
Study dates
26 Jul 2017to 28 Jan 2020
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 24 to 72 months
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Children with confirmed SCA who participated in the NOHARM study of hydroxyurea at the Mulago Hospital Sickle Cell Clinic (MHSCC), will be eligible for the MTD study after completing both 12-months of blinded study treatment and then an additional 12-months of open-label hydroxyurea for the second year of the study.
  • The age range for enrollment into NOHARM, which began in 2014, was 1-4 years. Therefore, the children who will be enrolled in the follow up MTD study will be 3-6 years of age.

Who cannot join

  • Not willing to come for all scheduled clinical visits or accept randomization

Trial locations and contacts

1 site in 1 country.

Uganda1 site

  • Mulago Hospital Sickle Cell Clinic

    Kampala

Other trials in Uganda

About this study

Official title: Optimizing Hydroxyurea Therapy in Children With Sickle Cell Anemia In Malaria Endemic Areas: The NOHARM Maximum Tolerated Dose (MTD) Study

The Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM) study is the first placebo-controlled randomized clinical trial of hydroxyurea treatment in a malaria endemic region. NOHARM has now achieved full enrollment; all children have completed the blinded portion of the protocol and are in the open-label study treatment portion.

This extension study of maximum tolerated dose (MTD), addresses the next critical set of questions about the optimal dosing and monitoring of hydroxyurea treatment for children with SCA in low-resource settings. By providing guidance about optimal hydroxyurea treatment, the NOHARM MTD Study will directly inform policies that can transform the health of African children living with SCA.

Read the detailed description

All children enrolled in NOHARM received hydroxyurea treatment at a fixed daily dose of 20 mg/kg/day. This dose was selected as a likely safe dose, but does not escalate hydroxyurea to MTD as is commonly done in the US. Without this information, we cannot know whether hydroxyurea treatment at the MTD would be feasible (since it requires closer monitoring to avoid hematological toxicities), safe (since adverse events may be greater with MTD, risk of malaria may be altered by MTD, and risk of infections as a result of neutropenia could also be greater with MTD) or beneficial (MTD is associated with higher hemoglobin and fetal hemoglobin concentration).

In this extension MTD study of open-label hydroxyurea for children in NOHARM who complete the initial study, consented children will be randomized to either fixed-dose or MTD hydroxyurea treatment for a minimum of 24 months. If hydroxyurea treatment continues to prove safe and effective in this low-resource malaria endemic area, and an optimal dosing scheme is determined, then the long-term goal is for all study children to transition to hydroxyurea treatment provided through the Ugandan Ministry of Health. To provide for a smooth transition, we will continue all children at either MTD or fixed dose hydroxyurea until a common end date (November 2019), at which time all study participants will have received a minimum of 24 months of additional hydroxyurea (either MTD or fixed dose). Addmedica, the Paris-based pharmaceutical company that provides the current active drug and placebo for the NOHARM trial, has agreed to provide additional hydroxyurea for this MTD study at no cost to the study or the participants.

The Specific Aims of the NOHARM MTD proposal include two initiatives for participants who are currently enrolled in NOHARM:

Aim 1. To determine the safety and efficacy of maximum tolerated dose (MTD) vs. fixed dose (20 mg/kg/day) hydroxyurea treatment in children with SCA in a low-resource, malaria endemic setting. For safety, we will compare adverse events and severe adverse events, including hematologic toxicities. For efficacy, we will assess hemoglobin level, fetal hemoglobin percentage (% HbF), and incidence of vaso-occlusive events such as pain crisis and acute chest syndrome.

Aim 2. To compare the clinical outcomes of MTD vs. fixed dose hydroxyurea treatment in children with SCA in a low-resource, malaria endemic setting. Clinical outcomes assessed will include growth and malaria incidence over a 24-month follow-up period, and differences in renal, splenic, and cerebrovascular function between study entry and 24-month follow-up.

Being tested
Hydroxyurea
Keywords
Hydroxyurea
Medical subject headings
Anemia, Sickle Cell, Malaria

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • HydroxyureaDrug

    Also called Siklos, Hydroxycarbamide

    Administered once a day in tablet form (100mg or scored 1000mg) for 24 months

Study groups in NCT03128515
Study groupRoleWhat they receive
MTD Dose EscalationExperimentalMaximum tolerated dose of Hydroxyurea, 25-30 mg/kg/day
Receives: Drug: Hydroxyurea
Fixed DoseActive comparatorFixed dose of Hydroxyurea, 20 mg/kg/day
Receives: Drug: Hydroxyurea

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Proportion of children with average hemoglobin ≥9.0 g/dL or average HbF ≥20%

    Proportion of children who achieve either an average hemoglobin ≥9.0 g/dL or an average HbF ≥20% after 24 months on study drug

    Measured: Over 24 month period on study drug

Secondary outcomes (11)

  1. Clinical malaria incidence

    Clinical malaria is defined as a history of fever or measured axillary temperature ≥37.5 degrees, plus Plasmodium species on blood smear.

    Measured: Over 24 month period on study drug

  2. Vaso-occlusive crises

    SCA-related adverse events defined as:

    • Pain event
    • Dactylitis
    • Acute chest syndrome

    Measured: Over 24 month period on study drug

  3. Incidence of severe adverse events (SAE)

    Death, hospitalization >7 days, life-threatening event

    Measured: Over 24 month period on study drug

  4. Incidence of hematologic toxicities

    Hematologic toxicities are defined as:

    • Hemoglobin (Hb) <4.0g/dL
    • Hb <6.0g/dL AND absolute reticulocyte count (ARC) <100 x 10E9/L
    • Hb <7.0g/dL AND ARC <80 x 10E9/L
    • Platelets <80 x 10E9/L
    • Absolute neutrophil count (ANC) <1.0 x 10E9/L

    Measured: Over 24 month period on study drug

  5. Cerebrovascular function

    Transcranial Doppler blood vessel velocity to determine cerebrovascular function

    Measured: At study treatment initiation then at 12 months and 24 months after study initiation

  6. Change in creatinine levels

    Changes in creatinine level as a measure of renal function

    Measured: Over 24 month period on study drug

  7. Change in cystatin C

    Changes in cystatin C level as a measure of renal function

    Measured: Over 24 month period on study drug

  8. Change in splenic function

    Quantitative micronuclei [Howell Jolly bodies] measured by flow cytometry

    Measured: Over 24 month period on study drug

  9. Change in height-for-age z-score

    Change in height-for-age z-score

    Measured: Over 24 month period on study drug

  10. Change in weight-for-age z-score

    Change in weight-for-age z-score

    Measured: Over 24 month period on study drug

  11. Change in weight-for-height z-score

    Change in weight-for-height z-score

    Measured: Over 24 month period on study drug

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Apr 2017
  2. Study start26 Jul 2017
  3. Primary completion7 Apr 2019
  4. Study completion28 Jan 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
187 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03128515
Sponsor's protocol ID
00456728
Acronym
NOHARM-MTD
Status last verified
Feb 2020
First submitted
22 Mar 2017
Last updated
20 Feb 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • John CC, Opoka RO, Latham TS, Hume HA, Nabaggala C, Kasirye P, Ndugwa CM, Lane A, Ware RE. Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa. N Engl J Med. 2020 Jun 25;382(26):2524-2533. doi: 10.1056/NEJMoa2000146.

    PubMed 32579813

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Hydroxyurea in people with Sickle Cell Anemia and Sickle Cell Disease, run by Indiana University at 1 site in Uganda.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 20 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Uganda. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of children with average hemoglobin ≥9.0 g/dL or average HbF ≥20% (time frame: Over 24 month period on study drug). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03128515, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Feb 2020.

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