Study Chronology

Date Event
June 1, 2001 Investigators from UNC and Malawi submit proposal to CDC in response to Request for Proposals
October 1, 2001 Funding begins
May-July, 2002 Formative research in Lilongwe is conducted
February-March 2003 GSK , Roche, BMS, and Boehringer Ingelheim agree to provide study drugs
May 6-June 27, 2003 Initial review by CDC, Malawi and UNC IRBs of Version 1.0 of Protocol (version date: April 16, 2003)
June 9, 2003 The DSMB reviews protocol and recommends that the trial go forward
September 15, 2003* First version of protocol approved by all 3 IRBs after responses to respective IRB reports
January 12, 2004 Pre-enrolment Study Visit by external monitor
March 10, 2004*  Amendment 1 (version Nov17, 2003)
i. Reconcile all recommendations from the 3 IRBs differences in approved protocols across the 3 ruling IRBs
ii. Include changing the starting the medications to birth instead of 7 days
March 18, 2004 CDC approves starting enrollment of pregnant women.
April 22, 2004 First baby born (Apr 21) and first treatment assignment (Apr 22)
June 15, 2004 DSMB reviews accrual
September 28, 2004*  Amendment 2 (version June 8, 2004) 
i. Split the one-stage consent process into 2 separate: Screening and Enrollment
ii. Anticipating and preventing hepatic toxicity due to nevirapine by modifying management of asymptomatic elevated transaminases
November 3, 2004* Amendment 3 (Version Sep 08, 2004) 
i. Correcting the dose of the second line infant regimen.
ii. Adjusting the toxicity table related to neutropenia to account for differences in an African population
February 2, 2005 DSMB reviews data as of Nov 15, 2004
February 7, 2005 Amendment 5 (Version Dec 03, 2004) 
Notification of Maternal ARV switch from nevirapine to second line drug (nelfinavir) in light of FDA advisory and advisory, and  hepatic toxicities.  CDC IRB required this notification be labeled an amendment. (Note that amendment 6 reflects the permanent replacement for maternal nevirapine)
March 15, 2005*
 
Amendment 4 (Version Dec 03, 2004) 
i. Addition to the maternal antiretroviral (ARV) regimen an extra 7 days to prevent development of nevirapine resistance. 
ii. Additional follow-up of infants found to be HIV-infected for safety monitoring and development of resistance development.
June 28, 2005 DSMB receives update on accrual
July 29, 2005* Amendment 6 (Version Jun 08, 2005) 
i.  Lopinavir/ritonavir to replace nevirapine in maternal ARV regimen
ii. Modify serious adverse event reporting by highlighting those which need to be reported in an expedited manner
Oct 25, 2005 DSMB receives update on accrual
January 9, 2006* Amendment 7 (Version Nov 04, 2005) 
Reimbursement increase to US$4
Jan 31, 2006 DSMB reviews data on visits as of Nov 30, 2005 and recommends analyzing all infant infections who were uninfected at birth
April 20, 2006*  Amendment 8 (Version Mar 08, 2006) 
i. Update DAIDS Toxicity Table
ii. Drop mothers’ dietary recall at 28 weeks
November 1, 2006*  Amendment 9 (Version May 12, 2006) 
i. CD4 count eligibility: enroll only if >250
ii. Drop mothers’ dietary recall at 32 and 48 weeks
iii. Accept CD4 count from antenatal CTA program
iv. Eliminate antenatal anthropometric measurements after taken at baseline
Dec 15, 2006 DSMB reviews data as of Sept 30, 2006
June 14, 2007 DSMB reviews data as of January 31, 2007 and requests an early review in September
July 27, 2007*  Amendment 10 (Version May 25, 2007) 
i.  Kaletra changed to Aluvia
ii.  Consents to seek permission to contact participants after study ends
iii.  Hepatitis substudy on stored specimens
Sept 10, 2007  DSMB reviews data as of June 30, 2007 with particular reference to the recent results from the SWEN Study
September 21, 2007* Amendment 11 (Version July 9, 2007) 
i. Consents to obtain permission to contact after end of study
January 7, 2008*  Amendment 12 (Version Nov 16, 2007) 
i. Updated timepoints for hepatitis substudy
March 26, 2008 DSMB meets and recommends stopping enhanced control arm and continuing to randomize to two intervention arms
March 27, 2008 In response to stopping enhanced control arm, the team did the following:
i.  Notify three IRBs
ii. Notify study participants. Those on control arm given choice of switching arms
iii.  New study participants are read a statement of the findings and told they will only receive the intervention arms
iv.  CDC GAP, WHO, NICHD, NIAID, ANRS are notified
June 16, 2008* Amendment 13 (Version May 2, 2008) 
i.  Study design changed to 2 x 2 factorial;  dropping enhanced control arms
ii. Reimbursement increased to $5 for regular visits
Feb 27, 2009 Last mother infant pair receives treatment assignment
April 29, 2009 The statistical team present the data as of April 8th and the decision is made to submit the data as a late breaker to the IAS Meeting in Cape Town.

                                        *Date approved by the last of the three IRBs (CDC, Malawi, UNC)