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The Saints went in front after they fooled the Colts with a fake field goal that eventually led to a Khiry Robinson rushing touchdown from one yard out.
It would get worse for the home team as Griff Whalen, part of the squad that fluffed the fake punt against the New England Patriots last week, fumbled the kickoff and Saints quarterback Drew Brees found Michael Hoomanawanui for the 16-yard score moments later, although Kai Forbath missed the extra point.
Luck was picked off for the second time just before the half as defensive back Kyle Wilson jumped the route and helped keep the home side scoreless in the first half.
New Orleans continued to pile on the pressure in the second half as Mark Ingram completed a solid drive with a one-yard touchdown to go up 27-0 early in the third quarter.
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The Colts replied with their first score of the game after Luck passed it deep to TY Hilton for an 87-yard touchdown to bring the AFC South team back in the game.
That same connection would combine again just before the end of the third quarter as Hilton hauled in a pass for a 46-yard score to make it a 13-point game.
Indianapolis made a real game of things late in the fourth quarter as Luck got his third touchdown pass of the game as he hit Donte Moncrief in the endzone to make it a six-point game with just under four minutes remaining.
The home team then failed to convert a late onside kick and without any time outs, the Saints managed to hold for the victory.
That makes the Saints 3-4 on the season while the Colts drop to the same record but still lead the AFC South, a division without a team above .500.