Prednisone Plus Chloroquine for the Treatment of Hyper-reactive Malarial Splenomegaly (LiHMS)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Oriol Mitja, Lihir Medical Centre
ClinicalTrials.gov Identifier:
NCT01785979
First received: February 5, 2013
Last updated: February 18, 2013
Last verified: February 2013
  Purpose

This randomized clinical trial will address a complication related to recurrent episodes of malaria in endemic areas - hyper-reactive malarial splenomegaly. We aim to assess the efficacy of chloroquine after prednisone-induction therapy compared to standard treatment of chloroquine alone in the treatment of adult patients with newly diagnosed hyper-reactive malarial splenomegaly.


Condition Intervention Phase
Hyper-reactive Malarial Splenomegaly
Malaria
Anaemia
Drug: prednisone induction - chloroquine
Drug: Chloroquine
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Prednisone Plus Chloroquine Versus Chloroquine for the Treatment of Hyper-reactive Malarial Splenomegaly in Papua New Guinea: a Randomized Open-label Trial

Resource links provided by NLM:


Further study details as provided by Lihir Medical Centre:

Primary Outcome Measures:
  • composite clinical & immunological endpoint [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Clinical cure, defined as a sustained reduction in spleen size of at least 40% at the 12 month follow up examination, compared with the spleen size at the baseline examination. Immunological cure, defined as a two-fold decrease of total immunoglobulin M levels is also needed.


Secondary Outcome Measures:
  • 3 months intermediate clinical cure [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Reduction in spleen size of at least 40% at the 3 month follow up examination

  • 6 months intermediate clinical cure [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Reduction in spleen size of at least 40% at the 3 month follow up examination

  • Anaemia [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Incidence of HMS related-anemia defined by hemoglobin levels below 10 g/L at 12 months

  • Malaria episode [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    occurrence of an acute episode of malaria identified by passive-case detection in the hospital facilities during the follow up period.

  • Bacterial infection [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    occurrence of an acute bacterial infection identified by passive-case detection in the hospital facilities during the follow up period.


Estimated Enrollment: 30
Study Start Date: February 2011
Estimated Study Completion Date: February 2013
Estimated Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Prednisone induction - chloroquine
0.5 mg/Kg daily of prednisone for 4 weeks after randomization, 0.25 mg daily for weeks 5-6, 0.15 mg daily for week 7 and 2.5 mg daily for week 8 and chloroquine at a fixed dose (300 mg base per week) for months 1-12
Drug: prednisone induction - chloroquine
At study entry, the patients will undergo physical examination and laboratory tests, including blood cell count, malaria microscopy, immune-chromatographic test for malaria antigen, malaria serology titers, and serum protein studies with immunoglobulin M quantification, immune-fixation and immunoglobulin free light chains measurement. We will assess all participants at 1, 3, 6 and 12 months after enrollment. Clinical examination and routine laboratory tests are done every 3 months during the follow-up period. Immunoglobulin M quantification and malaria serology are done at baseline, and at month 12 visit.
Other Names:
  • Deltasone,
  • Orasone,
  • Prednicen-M
Active Comparator: chloroquine
chloroquine at a fixed dose (300 mg base per week) for months 1-12
Drug: Chloroquine
At study entry, the patients will undergo physical examination and laboratory tests, including blood cell count, malaria microscopy, immune-chromatographic test for malaria antigen, malaria serology titers, and serum protein studies with immunoglobulin M quantification, immune-fixation and immunoglobulin free light chains measurement. We will assess all participants at 1, 3, 6 and 12 months after enrollment. Clinical examination and routine laboratory tests are done every 3 months during the follow-up period. Immunoglobulin M quantification and malaria serology are done at baseline, and at month 12 visit.
Other Names:
  • Aralen
  • Resochin
  • Alchroquin

Detailed Description:

Hyper-reactive malarious splenomegaly (HMS) is a known chronic autoimmune complication in areas where malaria is endemic. Patients with HMS complain most commonly of abdominal swelling or pain from the enlarged spleen and the condition is defined using clear clinical and laboratory criteria. HMS appears benign in most patients when seen first but if untreated, it leads to severe anaemia and also acute bacterial infections. There is familiar and ethnic clustering suggesting genetic basis. High prevalence rates have been reported in certain areas of Papua New Guinea, and Venezuela, and HMS is also common in parts of sub-Saharan Africa, including Sudan and Ghana.

The treatment of HMS is still empirical since no randomized trials have been done so far. Long term anti-malarial chemoprophylaxis is deemed the mainstay of therapy, but the optimal drug-regimen and duration are unknown. Three to six months may pass before a response is observed, and relapses may occur when therapy is discontinued.

On the basis of the observed benefit in experimental studies, glucocorticoids have been used for severe hyper-reactive malarial splenomegaly in various case reports. Because these cases had a favourable outcome and the drug tolerability was good, prednisone has become an attractive therapeutic option for this disease. Central to the pathophysiology of HMS is the overproduction of Immunoglobulin M due to a functional CD8 T-cell defect and the consequent expansion and activation of B lymphocytes. Glucocorticoids may have an immediate effect due to inhibition of the sequestration of immunoglobulin coated red blood cells by the mononuclear phagocyte system and a later effect due to glucocorticoid-induced inhibition of antibody synthesis. We aim to assess the efficacy of chloroquine after prednisone-induction therapy compared to chloroquine alone in the treatment of adult patients with newly diagnosed hyper-reactive malarial splenomegaly.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Defining features of HMS including chronic massive splenomegaly (at least 10 cm below the costal margin); serum Immunoglobulin M elevated more than 3.1 g/L and high malarial antibody titres (above 640).
  • Evidence of the polyclonal nature of the lymphocytes by serum immunoglobulin free light chains.
  • Aged at least 18 years
  • Haemoglobin level of > 5 mg/d

Exclusion Criteria:

  • known allergy to chloroquine,
  • use of anti-malarial treatment within the preceding month,
  • suspected coexisting diseases in which glucocorticoids are contraindicated (e.g. diabetes mellitus, peptic ulcer disease or any acute infection as defined clinically), and
  • splenomegaly secondary to known infectious or haematological causes
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01785979

Locations
Papua New Guinea
Lihir medical Centre
Londolovit, New ireland province, Papua New Guinea
Sponsors and Collaborators
Lihir Medical Centre
Investigators
Principal Investigator: Oriol Mitja, PhD Lihir Medical Centre
  More Information

No publications provided

Responsible Party: Oriol Mitja, Senior Medical Officer, Lihir Medical Centre
ClinicalTrials.gov Identifier: NCT01785979     History of Changes
Other Study ID Numbers: LiHMS
Study First Received: February 5, 2013
Last Updated: February 18, 2013
Health Authority: Papua New Guinea: Medical Society of Papua New Guinea

Additional relevant MeSH terms:
Anemia
Malaria
Splenomegaly
Hematologic Diseases
Protozoan Infections
Parasitic Diseases
Hypertrophy
Pathological Conditions, Anatomical
Chloroquine
Chloroquine diphosphate
Prednisone
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antimalarials
Antirheumatic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Filaricides
Antinematodal Agents
Anthelmintics
Central Nervous System Agents

ClinicalTrials.gov processed this record on August 26, 2014