SNPMiner Trials by Shray Alag


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Report for Mutation K76T

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 4 clinical trials

Clinical Trials


1 Chloroquine and Sulfadoxine-Pyrimethamine Efficacy for the Treatment of Uncomplicated Falciparum Malaria in Blantyre, Malawi

The purpose of this research study is to find out how well chloroquine works as a drug to treat malaria in children, compared to the standard malaria treatment in Malawi. In preparation for a longer study of the malaria treatment medication chloroquine alone and in combination with other drugs, a shorter pre-study will be done to compare the anti-malarial effectiveness of chloroquine versus sulfadoxine-pyrimethamine (SP), the standard treatment in Malawi. Two hundred ten children, ages 6 months to 12 years, around Blantyre, Malawi, will be given standard dosing of either chloroquine or SP when they come to the Ndirande Health Centre with signs or symptoms consistent with malaria. The first 30 participants in each treatment group will remain under continuous observation at the health center so that the researchers can monitor their response to the medication until the infection goes away. The participants will be followed for 28 days to see if the the treatment works or fails.

NCT00125489 Malaria Plasmodium Falciparum Malaria Drug: chloroquine sulfate Drug: sulfadoxine/pyrimethamine
MeSH: Malaria Malaria, Falciparum

The secondary study endpoints are: (1) rates of early and late therapeutic failure; (2) rates of early and late parasitologic failure; (3) prevalence of chloroquine-resistance conferring pfcrt K76T mutation in pre-treatment infections; (4) rates of pre- and post-treatment pfcrt K76T mutation in cases of chloroquine treatment failure; (5) prevalence of SP-resistance conferring dhfr/dhps mutations in pre-treatment infections; (6) rates of pre- and post-treatment dhfr/dhps mutations in cases of SP treatment failure; (7) clearance time of parasitemia; (8) clearance time of fever; and (9) presence of post-treatment anemia. --- K76T ---

The secondary study endpoints are: (1) rates of early and late therapeutic failure; (2) rates of early and late parasitologic failure; (3) prevalence of chloroquine-resistance conferring pfcrt K76T mutation in pre-treatment infections; (4) rates of pre- and post-treatment pfcrt K76T mutation in cases of chloroquine treatment failure; (5) prevalence of SP-resistance conferring dhfr/dhps mutations in pre-treatment infections; (6) rates of pre- and post-treatment dhfr/dhps mutations in cases of SP treatment failure; (7) clearance time of parasitemia; (8) clearance time of fever; and (9) presence of post-treatment anemia. --- K76T --- --- K76T ---


2 Parasite Clearance Time and Time to Recurrent Infection Following Treatment With Artemether/Lumefantrine Among Children With Uncomplicated P. Falciparum Malaria Five Years After Wide Scale Use of the Drug in Tanzania

Plasmodium falciparum resistance against artemisinins has been confirmed in South-East Asia and it is expressed phenotypically as a slow rate of parasite clearance. Nonetheless, it is not known whether the problem exist in Tanzania. This study assessed parasite clearance time and time to recurrent infection following treatment with Artemether/Lumefantrine (AL) among children with uncomplicated malaria.

NCT01998295 Instantaneous Clearance Drug: Artemether/lumefantrine
MeSH: Infection

Time to clearance of parasites carrying Pfmdr 1 N86Y and Pfcrt K76T alleles was assessed by molecular genotyping using blood samples collected during the early phase of treatment.. Inclusion Criteria: - Age 6-120 months - Presence of asexual P. falciparum parasitaemia of 2000-200 000/μL - No general danger signs or severe malaria present - Hemoglobin ≥5 g/dL - History of fever within 24 hours or axillary temperature ≥ 37.5 degree Celsius - No other cause of fever is detectable - No severe malnutrition - Guardian/patient has consented Exclusion Criteria: - general danger signs or signs of severe falciparum malaria - severe malnutrition - febrile condition due to diseases other than malaria - regular medication which might interfere with antimalarial pharmacokinetics - contraindications to any medicine being used Inclusion Criteria: - Age 6-120 months - Presence of asexual P. falciparum parasitaemia of 2000-200 000/μL - No general danger signs or severe malaria present - Hemoglobin ≥5 g/dL - History of fever within 24 hours or axillary temperature ≥ 37.5 degree Celsius - No other cause of fever is detectable - No severe malnutrition - Guardian/patient has consented Exclusion Criteria: - general danger signs or signs of severe falciparum malaria - severe malnutrition - febrile condition due to diseases other than malaria - regular medication which might interfere with antimalarial pharmacokinetics - contraindications to any medicine being used Instantaneous Clearance Infection Artemether/Lumefantrine (AL) has been in wide scale use in Tanzania since 2007 as first line treatment for uncomplicated falciparum malaria. --- N86Y --- --- K76T ---

Detailed sampling allowed us to assess parasite clearance, and selection of Plasmodium falciparum multidrug resistance (Pfmdr) 1 N86Y and Plasmodium falciparum chloroquine resistance transporter (Pfcrt) K76T genes between different time points and its association with parasite clearance and recurrence. --- N86Y --- --- K76T ---

Primary Outcomes

Description: Time to parasite clearance was assessed by taking blood samples and examining it by light microscopy prior (0 hour) and during treatment at 4, 8, 12 hours and then 6 hourly until two consecutive negative blood slides.

Measure: Time to parasite clearance

Time: 72 hours

Secondary Outcomes

Description: Time taken for parasites to reappear in the peripheral blood of the participant after initial treatment was assessed during the 42 days of follow up from blood samples taken on days 14, 21, 28 and 42.

Measure: Time to recurrent infection

Time: 42 days

Other Outcomes

Description: Blood samples collect on filter papers prior (0 Hour), during and after medication at 4, 8, 12 and after every 6 hours until 72 hours and on day 7 were analyzed by PCR to assess parasite clearance. Parasite positivity after day 7 was considered as recurrent infection.

Measure: Time to parasite clearance

Time: 7 days

Description: Time to clearance of parasites carrying Pfmdr 1 N86Y and Pfcrt K76T alleles was assessed by molecular genotyping using blood samples collected during the early phase of treatment.

Measure: Time to alleles clearance

Time: 168 hours

3 Evaluating the Potential Role of Chloroquine in Preventing Infections During Elimination Campaigns: A Randomized, Single-blind, Placebo-controlled Trial in Asymptomatic Mozambican Adults

One of the proposed ideas for malaria elimination includes the use of drugs to interrupt malaria transmission by exhausting the human reservoir of infection. Theoretically, mass treatment of an entire population with a very effective and rapid-acting drug (for instance an ACT), followed by the administration of an effective prophylactic regime during a minimum of four weeks, so as to outlast the typical development period of Plasmodium parasites in Anopheline mosquitoes, could achieve the same objective. In this respect, chloroquine (CQ) would be an appropriate candidate. This drug exhibits two conditions that make it attractive for elimination campaigns: 1) It has been demonstrated to have an excellent safety profile, allowing for its use in all age groups including pregnant women and children; and 2) Its relatively long elimination half life (t1/2=1-2 months) can provide a long post-treatment prophylactic effect. Recent evidence suggests that CQ sensitivity may be returning in places where discontinuation has reduced the drug pressure to the parasite populations. In countries such as Malawi, P. falciparum seems to have regained full sensitivity to CQ, and molecular markers of antiCQ resistance have nearly disappeared. While this does not support the reintroduction of CQ as first line therapy, it does suggest that, if proven sensitive in a given area, it could play a prophylactic role in malaria elimination strategies when used in combination with other drugs or tools. Thus, we intend to evaluate the potential role of chloroquine in preventing infections during elimination campaigns by performing a randomized, single-blind, placebo-controlled trial in asymptomatic Mozambican adults. Choosing asymptomatic parasitaemic adult males from a malaria-endemic area as our study population introduces limited risks when administering a drug with an uncertain efficacy (47% efficacious in 2001-2002). In malaria-endemic areas, this age group has a remarkably low risk of developing severe disease (irrespective of clinical symptoms), and it is foreseeable that parasitemia may be well tolerated, and in certain cases, spontaneously cleared from the individual's blood as a result of the immune system. In the unlikely event of any clinical symptomatology appearing throughout the follow-up, individuals will be examined by a study clinician and treated immediately with the country's first-line malaria treatment (artemether-lumefantrine, Coartem ®).

NCT02698748 Malaria Drug: Chloroquine Drug: Placebo
MeSH: Malaria

Prevalence of chloroquine conferring pfcrt K76T mutation in pre-treatment infections. --- K76T ---

Rates of pre treatment pfcrt K76T mutation in cases of chloroquine treatment failure. --- K76T ---

Rates of post treatment pfcrt K76T mutation in cases of chloroquine treatment failure. --- K76T ---

Primary Outcomes

Description: the absence of parasitemia at the end of the trial's follow-up period (Day 28), regardless of axillary temperature, without having previously met any of the criteria for early and late treatment failure

Measure: Adequate parasitologic response (APR) to therapy

Time: 28 days after first day of drug intake

Secondary Outcomes

Description: Detection of parasites once the initial parasitemia has been cleared in the time period from day 1 to day 3 after first day of drug intake

Measure: Early parasitologic failure

Time: 1-3 days after first day of drug intake

Description: The detection of parasites in patients having cleared their initial parasitemia anytime from day 4 to day 28

Measure: Late parasitologic failure

Time: 4-28 days after first day of drug intake

Description: Proportion of the isolates detected with this specific mutation among isolates at baseline (before study drug initiation)

Measure: Prevalence of chloroquine conferring pfcrt K76T mutation in pre-treatment infections

Time: 0 days after first day of drug intake

Description: Proportion of the isolates detected with this specific mutation at baseline among cases with confirmed treatment failure those

Measure: Rates of pre treatment pfcrt K76T mutation in cases of chloroquine treatment failure

Time: 0 days after first day of drug intake

Description: Proportion of the isolates detected as new infections or recrudescent ones with this specific mutation

Measure: Rates of post treatment pfcrt K76T mutation in cases of chloroquine treatment failure

Time: 28 days after first day of drug intake

Description: time in hours until the clearance of parasitemia

Measure: Clearance time of parasitaemia

Time: 28 days after first day of drug intake

4 A Multicentre Randomised Comparative Clinical Trial of the Efficacy of Artesunate + Amodiaquine Versus Artemether-lumefantrine (Coartem®) for the Treatment of Uncomplicated Childhood Plasmodium Falciparum Malaria in Zanzibar

The primary objective of the study was to determine the PCR-APCR up to day 42 in children <60 months of age, weighing ≥5kg with uncomplicated malaria, treated with either artesunate+ amodiaquine (ASAQ) or artemether-lumefantrine (AL; Coartem®). Secondary objectives included: clinical and laboratory assessment of drug tolerability and safety, evaluation of possible correlation between drug bioavailability and clinical outcome, comparison of efficacy data with the pre-implementation "ACO I" study, parasite and fever clearance, gametocyte carriage, and possible selection of mutations related to quinoline resistance.

NCT03768908 Plasmodium Falciparum Malaria Drug: Artemether-lumefantrine Drug: Artesunate + Amodiaquine
MeSH: Malaria Malaria, Falciparum

Proportions of single nucleotide polymorphisms at pfmdr1 Y86N and pfcrt K76T determined by established AluI restriction-based PCR-RFLP.. Inclusion Criteria: - Weight ≥5kg - No general danger signs or severe malaria present (see 4.4.2.1 & 4.4.2.2) - History of fever within 24 hours OR axillary temperature ≥ 37.5Cº - No other cause of fever is detectable - No severe malnutrition - Patient has parasite counts between 2000-200,000/ul (50-5000/200 white blood cells) - Guardian/Patient has understood the procedures of the study and is willing to participate - Patient able to come for stipulated follow up visits and has easy access to the Study Site Exclusion Criteria: General Danger Signs and Complications: - Not able to drink or breastfeed - Vomiting everything - Recent history of convulsions - Lethargic or unconscious - Unable to sit or stand (as appropriate for age) - History of allergy to test drugs - History of intake of any drugs other than paracetamol and aspirin within 3 days Signs of Severe Malaria: - Altered consciousness - Repeated convulsions - Inability of oral intake - Severe anaemia (Hb <5gm/dl) - Difficulty in breathing (pulmonary oedema, Respiratory Distress Syndrome) - Shock (small pulse, cold extremities) - Hypoglycaemia - Haemoglobinuria (dark coloured urine or Coca-Cola urine) - Kidney failure (little or no urine in a well-hydrated patient) - Jaundice (yellow colouring of eyes) - Hyperpyrexia (temperature above 39.5ºC) in combination with other signs - Hyperparasitaemia (more than 5% red blood cells parasitized or >200,000 parasites/µl) - Spontaneous bleeding (Disseminated Intravascular Coagulation) Inclusion Criteria: - Weight ≥5kg - No general danger signs or severe malaria present (see 4.4.2.1 & 4.4.2.2) - History of fever within 24 hours OR axillary temperature ≥ 37.5Cº - No other cause of fever is detectable - No severe malnutrition - Patient has parasite counts between 2000-200,000/ul (50-5000/200 white blood cells) - Guardian/Patient has understood the procedures of the study and is willing to participate - Patient able to come for stipulated follow up visits and has easy access to the Study Site Exclusion Criteria: General Danger Signs and Complications: - Not able to drink or breastfeed - Vomiting everything - Recent history of convulsions - Lethargic or unconscious - Unable to sit or stand (as appropriate for age) - History of allergy to test drugs - History of intake of any drugs other than paracetamol and aspirin within 3 days Signs of Severe Malaria: - Altered consciousness - Repeated convulsions - Inability of oral intake - Severe anaemia (Hb <5gm/dl) - Difficulty in breathing (pulmonary oedema, Respiratory Distress Syndrome) - Shock (small pulse, cold extremities) - Hypoglycaemia - Haemoglobinuria (dark coloured urine or Coca-Cola urine) - Kidney failure (little or no urine in a well-hydrated patient) - Jaundice (yellow colouring of eyes) - Hyperpyrexia (temperature above 39.5ºC) in combination with other signs - Hyperparasitaemia (more than 5% red blood cells parasitized or >200,000 parasites/µl) - Spontaneous bleeding (Disseminated Intravascular Coagulation) Plasmodium Falciparum Malaria Malaria Malaria, Falciparum All children in the right age group presenting with clinical signs of malaria at the study site were considered possible study subjects. --- Y86N --- --- K76T ---

The pfmdr1 Y86N and pfcrt K76T genes' Single Nucleotide Proteins (SNPs) analysis was done according to established AluI restriction-based PCR-RFLP protocols. --- Y86N --- --- K76T ---

Primary Outcomes

Description: Comparing PCR adjusted parasitological cure rate (PCR-APCR) between the two treatment options up to day 42. Parasitological cure will be adjusted using PCR genotyping of msp2 marker. Recrudescence is defined as the presence of at least one matching allelic band, and reinfection as the absence of any matching allelic band on day 0 and day of recurring parasitaemia. Patients with recurrent parasitaemia having missing filter paper sample or negative PCR results will be considered uncertain with regards to PCR adjusted outcome.

Measure: PCR adjusted parasitological cure rates by day 42

Time: 42 days

Secondary Outcomes

Description: Comparing proportion of response outcomes according to standard WHO classification i.e., cure rates on days 14, day 28 and 42. Defined as the absence of both re-parasitaemia and clinical symptoms suggestive of severe malaria during follow-up to the respective days.

Measure: The clinical and parasitological response outcome (i.e. cure rates) on days 14, day 28 and 42.

Time: 42 days

Other Outcomes

Description: Proportion of patients reporting any adverse event (AE) in the two study arms. The intensity of an adverse event was determined according to the following definitions: mild, moderate, severe, unknown. AEs were be categorized according to if there is a likely causal relationship between the event and the medical products: probably, possibly, unlikely.

Measure: Clinical and laboratory assessment of drug tolerability and safety i.e., incidence of adverse events.

Time: 42 days

Description: Fever clearance was determined by a medical doctor/officer who measured the patient's axillary temperature using an electronic thermometer and took a detailed clinical history as well as performed a clinical examination. All details were recorded in the CRF.

Measure: Fever clearance in the two study arms

Time: 42 days

Description: Clearance of parasites and gametocyte carriage were determined by Giemsa stained thick blood films were examined using electrical or sunlight microscope at the study site by an experienced microscopist. The number of parasites were calculated as the number of parasites seen against 200 leucocytes in the thick blood film and recorded in the CRF for the correct occasion. The slides were stored for quality controls, 10% of all slides were double-checked centrally.

Measure: Parasite clearance and gametocyte carriage in the two study arms

Time: 42 days

Description: Proportions of single nucleotide polymorphisms at pfmdr1 Y86N and pfcrt K76T determined by established AluI restriction-based PCR-RFLP.

Measure: Proportion of mutations related to Quinoline resistance at day0 and day of recurrent infection in the two study arms

Time: 42 days


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