IVM Alone vs ALB + IVM Against Onchocerciasis
Condition: Onchocerciasis
MeSH terms: Onchocerciasis
Study type: Interventional
Phase: Phase 3

Summary: 
      Onchocerciasis is a vector-borne nematode parasitic disease that causes severe disability.
      Onchocerciasis affects approximately 33 million people, mostly in 30 countries in sub-Saharan
      Africa (with small foci in Latin America and Yemen) 1This disease causes blindness and severe
      skin disease and it is spread by black flies. O. volvulus adult worms live in subcutaneous
      nodules. O. volvulus adult worms are larger and less sensitive to available drug treatments
      than those of the species that cause Lymphatic Filariasis (LF). They also have a longer
      lifespan (approximately 14 years rather than the estimated 7 years for LF parasites). Several
      programs and developments have greatly improved the Onchocerciasis. situation since the
      1970's when the Onchocerciasis Control Programme (OCP) in West Africa (green countries in the
      map) was initiated. OCP relied exclusively on vector (black fly) control in its early years.
      However, following the appearance of Ivermectin (Mectizan) on the scene in the late 1980's,
      OCP transitioned to become a drug distribution program with annual IVM MDA in 11 countries.
      OCP ended in 2002. This was replaced by the African Program for Onchocerciasis Control (APOC)
      which coordinates community directed distribution of IVM MDA in 28 African countries
      (including the former OCP countries). OCP and APOC have done a good job of reducing parasite
      infection intensities and Onchocerciasis disease rates in many endemic countries.
      Unfortunately, there is no real end in sight for the APOC approach (apart from a funding
      endpoint in 2015); while it may be possible to eliminate Onchocerciasis. In selected areas by
      MDA with IVM (alone, or combined with vector control), disease control programs in most
      African countries will require active maintenance for many years to come. While IVR has good
      activity against the parasite larvae that cause disease in the skin and eye (microfilariae or
      Mf), it does not kill O. volvulus adult worms, and they resume production of Mf that can lead
      to transmission of new Onchocerciasis. Cases by black flies after a few months. APOC
      activities are focused on areas with high infection rates (where disease risks are highest).
      However, extensive areas in Africa where fewer than 20% of adult men have Onchocerciasis
      nodules detectable by palpation are not receiving interventions for Onchocerciasis at this
      time. These areas are not disease free. (Onchocerciasis dermatitis can be severe in
      hypoendemic areas), and they also may serve as a source for reintroduction of the parasite
      into previously controlled areas after interventions stop.
    

Detailed description: 
      Onchocerciasis control programs have relied on annual MDA with IVM at a dose of 150-200
      µg/kg. This regimen kills skin (and eye) Mf, thereby reducing disease and (in some areas)
      transmission. However, standard IVM monotherapy has little macrofilaricidal activity against
      adult O. volvulus, and it does not permanently sterilize adult worms, which have a
      reproductive life span of 12-14 years. More effective drugs or dosing schedules that have
      embryo-static or macrofilaricidal activity could drastically reduce the number of years
      required to interrupt transmission of Onchocerciasis. IVM has activity against adult O.
      volvulus when it is given at high doses four times per year for several years. This regimen
      caused some adverse events, and is not practical for national control programs. By contrast,
      whereas ALB has little effect on O. volvulus Mf, the drug has embryo-toxic effects at
      standard doses manifest as partial suppression (by 66%) of skin Mf counts for at least one
      year. ALB given at doses of 800 mg produced a more sustained reduction in Mf relative to a
      dose of 400 mg, but higher doses did not improve efficacy. It is not known whether ALB
      produces transient or permanent female worm sterility. Administration of a single 400 mg dose
      of ALB combined with IVM 200 µg/kg failed to a show greater reduction in Mf or
      macrofilaricidal activity compared to IVM alone; however, combination therapy suppressed
      embryogenesis more than IVM alone. These studies involved small numbers of participants, used
      ALB only at a dose of 400 mg, and followed the participants for just one year. Thus, IVM
      combined with ALB at higher doses given more than once per year may generate more sustained
      reduction in Mf by reducing female fertility or by killing adult worms.

      IVM and ALB are very safe and highly effective anti-filarial drugs when given singly or in
      combination.

      ALB causes degenerative alterations in the tegument and intestinal cells of the worm by
      binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or
      assembly into microtubules. The loss of cytoplasmic microtubules leads to impaired uptake of
      glucose by larval and adult stages of the parasite, and depletes glycogen stores.
      Degenerative changes in endoplasmic reticulum and mitochondria of the germinal layer, and the
      subsequent release of lysosomal enzymes result in decreased production of adenosine
      triphosphate, which is the source of energy required for survival of the helminth. Due to
      diminished energy production, the parasite is immobilized and eventually dies. The drug has
      been shown to cause occasionally (<1% of treated patients) reversible reductions in total
      white blood cell count. It has also been associated with slight increases in liver
      transaminases in ~16% of patients. The enzymes return to normal levels with cessation of
      treatment. These abnormalities are associated primarily with prolonged treatment for such
      diseases as neurocysticercosis and hydatid diseases, not single dose treatment which is being
      proposed here. ALB given with fatty foods as proposed in the current protocol will increase
      absorption and may increase the risk of adverse side effects.

      IVMis an avermectin compound of macrocyclic lactones derived from the bacterium Streptomyces
      avermitilis. The mechanism by which IVM kills LF microfilariae is not known with certainty,
      but the drug interferes with glutamate gated ion channels that can affect parasite
      contractility and release of immunomodulatory molecules by the parasite. IVM also has a
      direct effect on the central nervous system and muscle function as it enhances strength of
      inhibitory neurotransmission pathways. The main concern with use of IVM in animals and humans
      is neurotoxicity, which can be manifest as ataxia. Neurotoxicity has not been observed in
      humans given single dose IVM for LF or other parasitic infections, and the drug has been used
      to treat millions of people with LF and Onchocerciasis. Peak IVM serum concentrations are
      reached approximately 4-5 hours after administration. The half-life of IVM in various
      populations ranges from 12 to 56 hours 12. There is no evidence of drug:drug interaction
      between ALB and IVM.

      IVM can cause nausea, dizziness and occasionally pruritus, but these are infrequent,
      transient and usually mild. Major side effects occur with heavy infections of Loa loa;
      however, this parasite is not endemic in Ghana.

      In Ghana the chiefs and elders are the custodians of the land so they must first to be
      contacted for permission to enter their communities. The study objectives and procedures are
      then explained to them, and if they accept it then the research team is allowed to enter the
      communities to explain the research aims and procedures to their subjects.
    

Intervention name(s): Ivermectin; Albendazole
Intervention type(s): Drug; Drug
Intervention description(s): Participants are either given Ivermectin alone or Ivermectin in combination with Albendazole; Albendazole will be given to participants in Arm 2 and 3 in combination with Ivermectin at varying time points.
Intervention MeSH terms: Ivermectin; Albendazole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention